Diaminopyrimidinecarboxamide derivative

ABSTRACT

A compound which may be used for the prevention or treatment of respiratory diseases in which STAT 6 is concerned, particularly asthma, chronic obstructive pulmonary disease and the like is provided. 
     A pyrimidine derivative or a salt thereof, which has an arylamino or arylethylamino group which may be substituted with a specified substituent, at the 2-position, amino group substituted with benzyl group or the like, at the 4-position, and carbamoyl group which may be substituted, at the 5-position, is provided.

TECHNICAL FIELD

The present invention relates to medicaments, particularly STAT 6(signal transducer and activator of transcription 6) inhibitors andnovel diaminopyrimidinecarboxamide derivatives useful as agents fortreating respiratory diseases in which STAT 6 is participated.

BACKGROUND OF THE INVENTION

It is known that asthma is a disease characterized by a reversibleairway obstruction which is accompanied by chronic inflammation andoverreaction of airway and that CD4⁺ T cells, particularly Th2 cell istaking an important role. It is known that Th2 cell is differentiatedfrom Thp cell by IL-4, and that IL-4 and IL-13 produced from Th2 cellcause airway contraction and chronic inflammation of airway throughinducing production of IgE antibody production, activation andinfiltration of eosinophil and increase of mucus secretion. In addition,it has been reported that IL-13 is also participated in the airwayepithelial hypertrophy and airway sub-epithelial fibrosis (J. Clin.Invest., 103, 6, 779-788, 1999), destruction of alveolus (J. Clin.Invest., 106, 1081-1093, 2000) and the like symptoms which are found inrespiratory diseases such as asthma, chronic obstructive pulmonarydisease (COPD) and the like.

STAT 6 (signal transducer and activator of transcription 6) isparticipated in the intracellular signal transduction of IL-4 and IL-13.It has been reported that differentiation of Th2 cell from Thp cell doesnot occur by the deletion of STAT 6 (Immunity, 4, 313-319, 1996) andthat production of IgE, acceleration of airway reactivity andinfiltration of eosinophil into airway and lung are inhibited in anasthma model of STAT 6 deletion mouse (J. Exp. Med., 187, 9, 1537-1542,1998). These reports suggest that STAT 6 participates in inflammatoryrespiratory diseases such as asthma and the like.

Also, It has been reported that STAT 6 and IL-4 mRNA in nasal mucosaincrease by administration of antigens to patients of allergic rhinitis(Clip. Exp. Allergy, 30, 86-93, 1709-1716, 2000) and also thatdermatitis-like symptoms such as infiltration of inflammatory cells intothe skin are induced by effecting over-expression of IL-4 in mice (J.Invest. Dermatol., 117, 4, 977-983 (2001)). These reports suggest thatSTAT 6 participates in allergic rhinitis and dermatitis.

STAT 6 is bonded to GYKXF motif of IL-4 receptor α chain (IL-4Rα) whichis a constituting factor of IL-4 receptor and IL-13 receptor (Science,165, 1265-1267, 1994), and a JAK family kinase is also bonded to thesereceptors. When IL-4 or IL-13 is bonded to a receptor, STAT 6 isdimerized by undergoing tyrosine-phosphorylation by the JAK familykinase and translocated into the nucleus where it exerts a function asthe transcription factor (Science, 165, 1265-1267, 1994). Accordingly,if any one of these steps, for example, the tyrosine-phosphorylation ofSTAT 6, can be inhibited, it becomes possible to inhibit the function ofSTAT 6 as a transcription factor so that its effectiveness is expectedin treating the aforementioned various diseases in which IL-4 and IL-13are participated.

Since Syk tyrosine kinase as a Zap/Syk family kinase classified into agenealogical relation different from the JAK family kinase based on thegene sequence genealogical tree (Genome Biology, 3, research0043.1-0043.12) mediates signals from antibody receptors (FcεRI, EcγR)and antigen receptors (BCR, TCR) and apoptosis inhibition signal ofeosinophil by GM-CSF, it has been reported that an Syk inhibitor isexpected as an agent for inflammations including asthma or allergicdiseases (e.g., Patent Reference 1). However, there are no reports onthe participation of Syk in the signals of IL-4 and IL-13. It isconsidered that an Syk inhibitor expresses its effect by inhibiting allof the activation via respective antigen receptors of B cell and T cell,inhibiting antibody production in the case of antibodies regardless oftheir subclasses and inhibiting differentiation of helper T cellnonspecifically. That is, it is predicted that Syk inhibitors alwaysaccompany inhibitory action of infection protection, immunologicalfunctions and the like. In the case of STAT 6 inhibitors on the otherhand, since the function of STAT 6 is specific for IL-4 and IL-13, theyspecifically inhibit production of IgE in the case of antibodies anddifferentiation of Th2 in the case of T cell subsets. Accordingly, it isexpected that STAT 6 inhibitors are effective as agents for treatingallergic or inflammatory respiratory diseases having less influencesupon infection protection, immunological function and the like (J. Clin.Inves., 109, 1279-1283, 2002).

Diaminopyrimidine-5-carboxamide derivatives useful for the treatment ofinflammatory and allergic diseases, immune diseases and the like basedon the Syk tyrosine kinase inhibition have been reported and, forexample, the following compound has been reported in Patent Reference 1.

(Z represents O, NR² or a bond and A represents a lower alkyl, aryl orthe like which may have a substituent(s), wherein —NH₂, —NH-lower alkyl,—N(lower alkyl)₂, —NH-lower alkylene-aryl, —NH-cycloalkyl, —NH-aryl,—NH-heteroaryl and the like are disclosed as substituents of said arylwhich may have a substituent(s), but they are not a saturated heteroring, and there is no illustrative disclosure of the3-chloro-4-hydroxyphenyl group as a substituent of the lower alkyl whichmay have a substituent. See said published application for details.)

However, there is no disclosure not only on the action of said compoundupon STAT 6 but also on its action upon IL-4 and IL-13. Also, since Syktyrosine kinase concerns itself in the signal transduction of B cell, Tcell, mast cell or the like when these cells are stimulated with anantigen, the effect of its inhibitor as an agent for treatinginflammatory diseases can be expected, but its immunosuppressive-effectsand the like must also be taken into consideration.

In addition, compounds having antiviral activities, includingdiaminopyrimidine-5-carboxamide derivatives, represented by thefollowing general formula have also been reported (e.g., PatentReference 2).

(X represents —NR³R⁴ or the like, Y represents —N(R⁶)— or the like, R¹represents —C(O)NR⁷R⁸ or the like and R⁵ represents aryl or the like,and said aryl may be substituted with —NR′R″, —R′ or the like, whereinsaid R′ and R″ represent hydrogen, (C1-C8)alkyl, aryl, aryl-(C1-C4)alkylor aryloxy-(C1-C4)alkyl, but they are not a saturated hetero ring, andthere is no disclosure on the illustrative compounds in which the R⁵—Ymoiety is 4-hydroxyphenethyl group. See said published application fordetails.)

Also, other pyrimidine-5-carboxamide derivatives useful as PDE 5inhibitors (e.g., Patent Reference 3; the 2-position substituent of thepiperidine ring is a lower alkylamino or indanylamino group which may besubstituted), NOS inhibitors (e.g., Patent Reference 4; imidazolylphenylgroup and 1,3-benzodioxol-5-yl group are essential), anticancer agents(e.g., Patent Reference 5; the 4-position substituent of the piperidinering is an amino group which is directly bonded to a ring group),anti-fugal agents (e.g., Patent Reference 6; an alkynyl group isessential on the 4-position substituent of the piperidine ring) and thelike have been reported, but all of them do not disclose or suggest onthe inhibitory activity for STAT 6 activation.

In addition, dihydrothiadiazole derivatives (e.g., Patent Reference 7),imidazopyrimidine derivatives (e.g., Patent Reference 8), benzofuranderivatives (e.g., Patent Reference 9), imidazo[2,1-b]thiazolederivatives (e.g., Patent Reference 10), tetrahydroquinoline derivatives(e.g., Patent Reference 11) and the like have been reported as STAT 6activation inhibitors, but there are no reports on pyrimidinederivatives.

-   Patent Reference 1-   International Publication No. 99/31073 pamphlet-   Patent Reference 2-   International Publication No. 99/41253 pamphlet-   Patent Reference 3-   International Publication No. 01/83460 pamphlet-   Patent Reference 4-   International Publication No. 01/72744 pamphlet-   Patent Reference 5-   International Publication No. 00/39101 pamphlet-   Patent Reference 6-   German Patent Application Publication No. 4029650 specification.-   Patent Reference 7-   JP-A-2000-229959-   Patent Reference 8-   International Publication No. 02/14321 pamphlet-   Patent Reference 9-   International Publication No. 02/53550 pamphlet.-   Patent Reference 10-   JP-A-11-106340-   Patent Reference 11-   International Publication No. 02/79165 pamphlet

Since inhibitors of STAT 6 activation are expected as agents fortreating respiratory diseases such as asthma, COPD and the like, greatdemand has been directed toward the development of novel compounds.

DISCLOSURE OF THE INVENTION

The present inventors have found that diaminopyrimidine-5-carboxamidederivatives partly disclosed in Patent Reference 1 have the inhibitoryactivity for STAT 6 activation. A compound having said inhibitoryactivity can be expected as an agent for treating respiratory diseasessuch as asthma, COPD and the like, having less suppressive effect onimmunological function, and also is useful as an agent for treatingother inflammatory and allergic diseases. Accordingly, intensive studieson the compounds having the inhibitory activity for STAT 6 activationwere conducted, with the aim of providing novel compounds which haveless side effects and are useful for the treatment of respiratorydiseases and the like and further providing medicaments containing them.As a result, a novel diaminopyrimidine-5-carboxamide derivative havingan aromatic ring group linked to the 2-position through a specifiedlinking arm and a substituted amino group on the 4-position was found,and it was found that said compound has a potent and selective STAT 6inhibitory activity, thereby accomplishing the present invention.

That is, the present invention relates to a STAT 6 activation inhibitorwhich comprises a diaminopyrimidinecarboxamide derivative represented bythe following formula (I) or a salt thereof as the active ingredient,

(symbols in the formula have the following meanings:

A¹: CR⁵ or N,

R⁵: —H, -lower alkyl, —O-lower alkyl or -halogen,

A²: CR⁶ or N,

R⁶: —H or -halogen,

R³: —R⁰, -lower alkyl substituted with halogen, -halogen, —OR⁰, —S-loweralkyl, —CO-lower alkyl, —CO₂-lower alkyl, -lower alkylene-OH, -heteroring, —O-hetero ring, —N(R⁰)-hetero ring, -lower alkylene-hetero ring,—O-lower alkylene-hetero ring, —S-lower alkylene-hetero ring, —SO-loweralkylene-hetero ring, —SO₂-lower alkylene-hetero ring, —N(R⁰)-loweralkylene-hetero ring, -lower alkylene-CO-hetero ring, -loweralkylene-N(R⁰)₂, —SO₂—N(R⁰)-lower alkyl or -loweralkylene-N(R⁰)—CO₂-lower alkylene-phenyl,

R⁰: the same or different from one another, and each is H or a loweralkyl,

n: 0 or 2,R⁴: (i) when n=2, —R⁰, lower alkyl substituted with halogen, —OR⁰,—N(R⁰)—CHO, —N(R⁰)—CO-lower alkyl or —N(R⁰)—SO₂-lower alkyl,

(ii) when n=0, —H, lower alkyl substituted with halogen, —OH, —NH—CHO,—CON(R⁰)₂, -lower alkylene substituted with halogen-OH, -loweralkylene-NH₂, -lower alkylene-NHCONH₂, -lower alkylene-CO₂H, -loweralkylene-CO₂-lower alkyl, -lower alkylene-CN, or —CH(loweralkylene-OH)₂, or a group represented by a formula —X^(a)—R^(4a),

X^(a): single bond, —O—, —CO—, —S—, —SO₂—, —N(R⁰)—, —N(R⁰)CO—,—N(R⁰)SO₂—, -lower alkylene-O—, -lower alkylene-N(R⁰)—, -loweralkylene-N(R⁰)CO—, -lower alkylene-N(R⁰)SO₂—, -lower alkylene-N(R⁰)CO₂—,—N(CO—R⁰—, —N(SO₂-lower alkyl)-, —CON(R⁰)—, -lower alkylene-O—CO—,-lower alkenylene-CO—, -lower alkenylene-CON(R⁰)—, -loweralkenylene-CO₂—, —O—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—N(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CON(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)— or—N(R⁰)CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,

k and m, the same or different from each other, and each is 0, 1, 2, 3or 4,

R^(4a): lower alkyl, phenyl, hetero ring, cycloalkyl, loweralkylene-phenyl, lower alkylene-hetero ring, lower alkylene-OH, loweralkenyl, lower alkenylene-phenyl or lower alkenylene-hetero ring,

wherein the hetero rings in R³ and R^(4a) may be substituted with 1 to 5of lower alkyl, halogen, —OR⁰, —S-lower alkyl, —S(O)-lower alkyl,—SO₂-lower alkyl, lower alkylene-OR⁰, —N(R⁰)₂, —CO₂R⁰, —CON(R⁰)₂, —CN,—CHO, —SO₂N(R⁰)₂, —N(R⁰)—SO₂-lower alkyl, —N(R⁰)—CO—N(R⁰)₂,—N(R⁰)—CO₂-lower alkyl, —N(R⁰)—CO₂-cycloalkyl, —NH—C(═NH)—NH-loweralkyl, —NH—C(═N—CN)—NH-lower alkyl, hetero ring (said hetero ring may besubstituted with 1 to 5 substituents selected from lower alkyl, OH andlower alkylene-OH), -lower alkylene-NH—C(═NN)—NH₂, —O-phenyl,—CO-phenyl, —N(R⁰)—CO-lower alkyl, —N(R⁰)—CO-lower alkylene-N(R⁰)₂,-lower alkylene-N(R⁰)—CO-lower alkylene-N(R⁰)₂, —CO—N(R⁰)-loweralkylene-N(R⁰)₂, —CO-lower alkylene-N(R⁰)₂, —CO-lower alkylene-CO₂R⁰,-lower alkylene-N(R⁰)₂, -lower alkylene-CO₂R⁰, -loweralkylene-CO—N(R⁰)₂, -lower alkylene-N(R⁰)—CO—lower alkyl, -loweralkylene-N(R⁰)—CO₂-lower alkyl, -lower alkylene-N(R⁰)—SO₂-lower alkyl,-lower alkylene-hetero ring (said hetero ring may be substituted with 1to 5 substituents selected from lower alkyl, OH and lower alkylene-OH),lower alkylene-O-lower alkylene-phenyl, ═N—O—R⁰ or oxo, and phenyl andcycloalkyl may be substituted with 1 to 5 of lower alkyl, OH, O-loweralkyl or N(R⁰)₂, and

wherein the lower alkylene in R³, R⁴, R^(4a) and X^(a) may besubstituted with 1 to 5 of —OR⁰, —CO₂R⁰, —CON(R⁰)₂, —N(R⁰)₂, —N(R⁰)COR⁰or hetero ring, orR³ and R⁴ may together form *—N(R⁷)—(CH₂)₂—, *—(CH₂)₂, —N(R⁷)—,*—CH₂—N(R⁷)—CH₂—, *—N(R⁷)—(CH₂)₃—, *—(CH₂)₃—N(R⁷)—, *—CH₂—N(R⁷)—(CH₂)₂—,*—(CH₂)₂—N(R⁷)—CH₂—, *—C(O)—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—C(O)—,*—N(R⁷)—CH═CH—, *—CH═CH—N(R⁷)—, *—N═CH—CH═CH—, *—CH═N—CH═CH—,*—CH═CH—N═CH—, *—CH═CH—CH═N—, *—N═CH—CH═N—, *—CH═N—N═CH—, *—N(R⁷)—N═CH—,*—CH═N—N(R⁷)—, *—O—(CH₂)—O—, *—O—(CH₂)₃—O—, *—O—(CH₂)₂—N(R⁷)—,*—(CH₂)₂—C(O)—, *—CH═CH—C(O)—O— or *—N═C(CF₃)—NH—,

wherein * indicates bonding to the position shown by R³

R⁷: —H, -lower alkyl or —CO-lower alkyl,

B: H, lower alkenyl, lower alkynyl, lower alkyl substituted withhalogen, CN, S-lower alkyl, aryl which may have a substituent(s),cycloalkyl which may have a substituent(s) or hetero ring which may havea substituent(s),Y: single bond; or lower alkylene which may be substituted with 1 to 5groups selected from halogen, OH, O-lower alkyl, —NH₂, —NH-lower alkyland —N(lower alkyl)₂, and R¹ and R²: the same or different from eachother, and each represents H, lower alkyl or O-lower alkyl which mayhave a substituent(s)).

Also, according to the present invention, a Th2 cell inhibitor whichcomprises a diaminopyrimidinecarboxamide derivative or a salt thereof asthe active ingredient.

Also, the present invention relates to the use of thediaminopyrimidinecarboxamide derivative represented by formula (I) or asalt thereof for the manufacture of a STAT 6 activation inhibitor or aTh2 cell differentiation inhibitor. Also, the present invention relatesto a method for inhibiting activation of STAT 6 or a method forinhibiting differentiation of Th2 cell, which comprises administering aneffective amount of the diaminopyrimidinecarboxamide derivativerepresented by formula (I) or a salt thereof to a mammal.

The present invention also relates to a noveldiaminopyrimidinecarboxamide derivative represented by the followingformula (Ia) or a salt thereof, which is included in the compounds ofthe aforementioned formula (I), characterized in that it has at leastone saturated heterocyclic group in the R⁴ of formula (I).

(symbols in the formula have the following meanings:

A¹: CR⁵ or N,

R⁵: —H, -lower alkyl, —O-lower alkyl or -halogen,

R³: —R⁰, -lower alkyl substituted with halogen, -halogen, —OR⁰, —S-loweralkyl, —CO-lower alkyl, —CO₂-lower alkyl, -lower alkylene-OH, -saturatedhetero ring, —X^(b)-heteroaryl, —X^(b)-saturated hetero ring,—X^(b)-heteroaryl, -lower alkylene-N(R⁰)₂, —SO₂—N(R⁰)-lower alkyl or-lower alkylene-N(R⁰)—CO₂-lower alkylene-phenyl,

X^(b): -lower alkylene-, —O-lower alkylene-, —S-lower alkylene-,—SO-lower alkylene-, —SO₂-lower alkylene-, —N(R⁰)-lower alkylene- or-lower alkylene-CO—,

R⁰: the same or different from one another, and each represents H or alower alkyl,

R⁴: —X^(a)-saturated hetero ring, -lower alkylene-saturated hetero ringor -lower alkenylene-saturated hetero ring,

X^(a): single bond, —O—, —CO—, —S—, —SO₂—, —N(R⁰)—, —N(R⁰)CO—,—N(R⁰)SO₂—, -lower alkylene-O—, -lower alkylene-N(R⁰)—, -loweralkylene-N(R⁰)CO— or -lower alkylene-N(R⁰)SO₂—, -loweralkylene-N(R⁰)CO₂—, —N(CO—R⁰)—, —N(SO₂-lower-alkyl)-, —CON(R⁰)—, -loweralkylene-O—CO—, -lower alkenylene-CO—, -lower alkenylene-CON(R⁰)—,-lower alkenylene-CO₂—, —O—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—N(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m),—CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CON(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)— or—N(R⁰)CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,

k and m: the same or different from each other, and each is 0, 1, 2, 3or 4,

wherein the saturated hetero rings in R³ and R^(4a) may be substitutedwith 1 to 5 of lower alkyl, halogen, —OR⁰, —S-lower alkyl, —S(O)-loweralkyl, —SO₂-lower alkyl, lower alkylene-OR⁰, —N(R⁰)₂, —CO₂R⁰, —CON(R⁰)₂,—CN, —CHO, —SO₂N(R⁰)₂, —N(R⁰)—SO₂-lower alkyl, —N(R⁰)—CO—N(R⁰)₂,—N(R⁰)—CO₂-lower alkyl, —N(R⁰)—CO₂-cycloalkyl, —NH—C(═NH)—NH-loweralkyl, —NH—C(═N—CN)—NH-lower alkyl, saturated hetero ring (said heteroring may be substituted with 1 to 5 substituents selected from loweralkyl, OH and lower alkylene-OH), heteroaryl, -loweralkylene-NH—C(═NN)—NH₂, —O-phenyl, —CO-phenyl, —N(R⁰)—CO-lower alkyl,—N(R⁰)—CO-lower alkylene-N(R⁰)₂, -lower alkylene-N(R⁰)—CO-loweralkylene-N(R⁰)₂, —CO—N(R⁰)-lower alkylene-N(R⁰)₂, —CO-loweralkylene-N(R⁰)₂, —CO-lower alkylene-CO₂R⁰, -lower alkylene-N(R⁰)₂,-lower alkylene-CO₂R⁰, -lower alkylene-CO—N(R⁰)₂, -loweralkylene-N(R⁰)—CO-lower alkyl, -lower alkylene-N(R⁰)—CO₂-lower alkyl,-lower alkylene-N(R⁰)—SO₂-lower alkyl, -lower alkylene-hetero ring (saidhetero ring may be substituted with 1 to 5 substituents selected fromlower-alkyl, OH and lower alkylene-OH), lower alkylene-O-loweralkylene-phenyl, ═N—O—R⁰ or oxo, and phenyl and cycloalkyl may besubstituted with 1 to 5 of lower alkyl, OH, O-lower alkyl or N(R⁰)₂, and

wherein the lower alkylene in R³, R⁴ and X^(a) may be substituted with 1to 5 of —OR⁰, —CO₂R⁰, —CON(R⁰)₂, —N(R⁰)₂, —N(R⁰)COR⁰ or hetero ring, orR³ and R⁴ may together form *—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—,*—CH₂—N(R⁷)—CH₂—, *—N(R⁷)—(CH₂)₃—, *—(CH₂)₃—N(R⁷)—, *—CH₂—N(R⁷)—(CH₂)₂—,*—(CH₂)₂—N(R⁷)—CH₂—, *—C(O)—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—C(O)—,*—N(R⁷)—CH═CH—, *—CH═CH—N(R⁷)—, *—N═CH—CH═CH—, *—CH═N—CH═CH—,*—CH═CH—N═CH—, *—CH═CH—CH═N—, *—N═CH—CH═N—, *—CH═N—N═CH—, *—N(R⁷)—N═CH—,*—CH═N—N(R⁷)—, *—O—(CH₂)₂—O—, *—O—(CH₂)₃—O—, *—O—(CH₂)₂—N(R⁷)—,*—(CH₂)₂—C(O)—, *—CH═CH—C(O)—O— or *—N═C(CF₃)—NH—, wherein * indicatesbonding to the position shown by R³,

R⁷: —H, -lower alkyl or —CO-lower alkyl,

B: aryl which may have a substituent(s) or heteroaryl which may have asubstituent(s), andR¹ and R²: the same or different from each other, and each represents H,lower alkyl or O-lower alkyl which may have a substituent(s)).

In addition, the present invention also relates to a noveldiaminopyrimidinecarboxamide derivative represented by the followingformula (Ib) or a pharmaceutically acceptable salt thereof, which isincluded in the compounds of the aforementioned formula (I),characterized in that it has at least one saturated hetero ring group inthe R³ of formula (I).

(symbols in the formula have the following meanings:

A¹: CR⁵ or N,

R⁵: —H, -lower alkyl, —O-lower alkyl or -halogen,

R³: -saturated hetero ring or —X^(b)-saturated hetero ring,

X^(b): -lower alkylene-, —O—, —N(R⁰)—, —O-lower alkylene-, —S-loweralkylene-, —SO-lower alkylene-, —SO₂-lower alkylene-, —N(R⁰)-loweralkylene- or -lower alkylene-CO—,

R⁰: the same or different from one another, and each represents H or alower alkyl,

R⁴: —H, -lower alkyl substituted with halogen, —OH, —NH—CHO, —CON(R⁰)₂,-lower alkylene substituted with halogen-OH, -lower alkylene-NH₂, -loweralkylene-NHCONH₂, -lower alkylene-CO₂H, -lower alkylene-CO₂-lower alkyl,-lower alkylene-CN, —CH(lower alkylene-OH)₂ or —X^(a)—R^(4a),

X^(a): single bond, —O—, —CO—, —S—, —SO₂—, —N(R⁰)—, —N(R⁰)CO—,—N(R⁰)SO₂—, -lower alkylene-O—, -lower alkylene-N(R⁰)—,-lower-alkylene-N(R⁰)CO— or -lower alkylene-N(R⁰)SO₂—, -loweralkylene-N(R⁰)CO₂—, —N(CO—R⁰)—, —N(SO₂-lower alkyl)-, —CON(R⁰)—, -loweralkylene-O—CO—, -lower alkenylene-CO—, -lower alkenylene-CON(R⁰)—,-lower alkenylene-CO₂—, —O—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—N(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CON(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)— or—N(R⁰)CO)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,

k and m: the same or different from each other, and each is 0, 1, 2, 3or 4,

R^(4a): lower alkyl, phenyl, heteroaryl, cycloalkyl, loweralkylene-phenyl, lower alkylene-heteroaryl, lower alkylene-OH, loweralkenyl, lower alkenylene-phenyl or lower alkenylene-heteroaryl,

wherein the saturated hetero ring and heteroaryl in R³ and R^(4a) may besubstituted with 1 to 5 of lower alkyl, halogen, —OR⁰, —S-lower alkyl,—S(O)-lower alkyl, —SO₂-lower alkyl, lower alkylene-OR⁰, —N(R⁰)₂,—CO₂R⁰, —CON(R⁰)₂, —CN, —CHO,

—SO₂N(R⁰)₂, —N(R⁰)—SO₂-lower alkyl, —N(R⁰)—CO—N(R⁰)₂, —N(R⁰)—CO₂-loweralkyl, —N(R⁰)—CO₂-cycloalkyl, —NH—C(═NH)—NH-lower alkyl,—NH—C(═N—CN)—NH-lower alkyl, hetero ring (said hetero ring may besubstituted with 1 to 5 substituents selected from lower alkyl, OH andlower alkylene-OH), -lower alkylene-NH—C(═NN)—NH₂, —O-phenyl,—CO-phenyl, —N(R⁰)—CO-lower alkyl, —N(R⁰)—CO-lower alkylene-N(R⁰)₂,-lower alkylene-N(R⁰)—CO-lower alkylene-N(R⁰)₂, —CO—N—(R⁰)-loweralkylene-N(R⁰)₂, —CO-lower alkylene-N(R⁰)₂, —CO-lower alkylene-CO₂R⁰,-lower alkylene-N(R⁰)₂-lower alkylene-CO₂R⁰, -loweralkylene-CO—N(R⁰)₂-lower alkylene-N(R⁰)—CO-lower alkyl, -loweralkylene-N(R⁰)—CO₂-lower alkyl, -lower alkylene-N(R⁰)—SO₂-lower alkyl,-lower alkylene-hetero ring (said hetero ring may be substituted with 1to 5 substituents selected from lower alkyl, OH and lower alkylene-OH),-lower alkylene-O-lower alkylene-phenyl, ═N—O—R⁰ or oxo, and phenyl andcycloalkyl may be substituted with 1 to 5 of lower alkyl, OH, O-loweralkyl or N(R⁰)₂, or the lower alkylene in R³, R⁴, R^(4a) and X^(a) maybe substituted with 1 to 5 of —OR⁰, —CO₂R⁰, —CON(R⁰)₂, —N(R⁰)₂,—N(R⁰)COR⁰ or hetero ring, orR³ and R⁴ may together form *—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—,*—CH₂—N(R⁷)—CH₂—, *—N(R⁷)—(CH₂)₃—, *—(CH₂)₃—N(R⁷)—, *—CH₂—N(R⁷)—(CH₂)₂—,*—(CH₂)₂—N(R⁷)—CH₂—, *—C(O)—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—C(O)—,*—N(R⁷)—CH═CH—, *—CH═CH—N(R⁷)—, *—N═CH—CH═CH—, *—CH═N—CH═CH—,*—CH═CH—N═CH—, *—CH═CH—CH═N—, *—N═CH—CH═N—, *—CH═N—N═CH—, *—N(R⁷)—N═CH—,*—CH═N—N(R⁷)—, *—O—CH₂—O—, *—O—(CH₂)₂—O—, (CH₂)₃—O—, *—O—(CH₂)₂—N(R⁷)—,*—(CH₂)₂—C(O)—, *—CH═CH—C(O)—O— or *—N═C(CF₃)—NH—, wherein * indicatesbonding to the position shown by R³,

R⁷: —H, -lower alkyl or —CO-lower alkyl,

B: aryl which may have a substituent(s) or heteroaryl which may have asubstituent(s), andR¹ and R² the same or different from each other, and each represents H,lower alkyl or O-lower alkyl which may have a substituent (s)).

Further, the present invention also relates to a noveldiaminopyrimidinecarboxamide derivative represented by the followingformula (Ic) or a pharmaceutically acceptable salt thereof, which isincluded in the compounds of the aforementioned formula (I),characterized in that the amino group at 2-position is a (substitutedphenyl)ethylamino group.

(symbols in the formula have the following meanings:R⁵: —H or -halogen,B: phenyl which may have 1 to 3 substituents selected from lower alkyland halogen,Y: single bond or —CH₂—, andR¹ and R²: the same or different from each other, and each represents Hor lower alkyl which may have a substituent(s)).

Furthermore, the present invention also relates to a medicament whichcomprises a novel diaminopyrimidinecarboxamide derivative represented bythe aforementioned formula (Ia), (Ib) or (Ic) or a pharmaceuticallyacceptable salt thereof as the active ingredient, particularly apharmaceutical composition which is effective as a preventive ortherapeutic agent for respiratory diseases such as asthma, COPD and thelike.

The present invention is described in detail in the following.

The terms “alkyl”, “alkenyl”, “alkynyl”, “alkylene” and “alkenylene” asused herein mean straight chain form or branched form hydrocarbonchains. The “lower alkyl” is preferably a C₁₋₆ alkyl, more preferably aC₁₋₄ alkyl, further preferably C₁₋₃ alkyl such as methyl, ethyl,isopropyl or the like. The “lower alkylene” is preferably a C₁₋₆alkylene, more preferably a C₁₋₄ alkylene, further preferably a C₁₋₂alkylene. The “lower alkenyl” means that it has one or more double bondsat optional positions of a C₂₋₆ alkyl, The “lower alkynyl” means that ithas one or more triple bonds at optional positions of a C₂₋₆ alkylchain, and the “lower alkenylene” means that it has one or more doublebonds at optional positions of a C₂₋₆ alkylene.

The “halogen” represents F, Cl, Br and I, preferably F, Cl and Br.

The “lower alkyl substituted with halogen” is a lower alkyl substitutedwith one or more of halogen, preferably a C₁₋₂ alkyl having from 1 to 5F, and its examples include fluoromethyl, difluoromethyl,trifluoromethyl and trifluoroethyl. The “lower alkylene substituted withhalogen” is a lower alkylene substituted with one or more of halogen,preferably a C₁₋₃ alkylene having from 1 to 6 F.

Preferred as the “aryl group” is a monocyclic to tricyclic aryl grouphaving from 6 to 14 carbon atoms. More preferred are phenyl and naphthylgroups. In addition, a five- to eight-membered cycloalkyl ring may befused with phenyl group to form, for example, indanyl,tetrahydronaphthyl or the like. The “cycloalkyl group” is a cycloalkylgroup having from 3 to 12 carbon atoms, and it may form a bridged ringor spiro-ring. Preferred are cycloalkyl groups having from 3 to 10carbon atoms, and more preferred are cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl and norbornyl.

The “cycloalkylene” means a divalent group formed by removing onehydrogen atom at an optional position of “cycloalkyl group”, and itsexamples include cyclohexane-1,4-diyl, cyclohexane-1,1-diyl,cyclopentane-1,1-diyl and the like.

The “saturated hetero ring” represents a 4- to 8-membered saturatedmonocyclic hetero ring group containing 1 to 4 hetero atoms selectedfrom O, S and N, and a bicyclic or tricyclic hetero ring group in whichsaid saturated monocyclic hetero rings are fused each other, or amonocyclic hetero'ring is fused with a cycloalkyl ring(s). It may forman oxide or dioxide through the oxidation of S or N as a ring atom, ormay form a bridged ring or a spiro-ring. Their preferred examplesinclude saturated hetero rings such as piperidyl, morpholinyl,thiomorpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl,pyrrolidinyl, oxazolidinyl, thiazolidinyl, homopiperazinyl,tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, homomorpholinyl andthe like, or bridged rings such as 2,5-diazabicyclo[2,2,1]heptyl,2,8-diazaspiro[4,5]decane and the like.

The “heteroaryl” represents a 5- or 6-membered monocyclic heteroarylcontaining 1 to 4 hetero atoms selected from O, S and N, and a bicyclicor tricyclic hetero ring group in which (i) heteroaryl groups eachother, (ii) heteroaryl and cycloalkyl ring, (iii) heteroaryl and benzenering, (iv) saturated hetero ring and heteroaryl or (v) saturated heteroring and benzene ring are fused. It may form an oxide or dioxide throughthe oxidation of S or N as a ring atom, or may form a bridged ring orspiro-ring. Preferably, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl,benzothienyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, chromanyl,quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pyrrolidinyl and thelike may be exemplified.

The “hetero ring group” includes the aforementioned “saturated heteroring” and “heteroaryl” and “partially unsaturated hetero ring” such asdihydropyridyl, dihydropyrrolyl, dihydroxazolyl, dihydrothiazolyl,dihydroimidazolyl, tetrahydropyrimidinyl and the like.

The term “which may have a substituent(s)” means “not substituted” or“substituted with the same or different 1 to 5 substituents”.

The substituent in the “cycloalkyl which may have a substituent(s)” is agroup which may be used as a substituent of these rings, and ispreferably a group selected from the following group G.

Group G: -lower alkyl, —OH, —O-lower alkyl, -aryl, -hetero ring and oxo.

The substituent in the “aryl which may have a substituent” and “heteroring which may have a substituent(s)” is a group which may be used as asubstituent(s) of these rings, and is preferably a group selected fromthe following group P.

Group P: -lower alkyl which may be substituted with a group of group Q,-lower alkyl substituted with halogen, -halogen, —OH, —CN, —O-(loweralkyl which may be substituted with a group of group Q), —O-lower alkylsubstituted with halogen, —S-lower alkyl, —NH₂, —NH-(lower alkyl whichmay be substituted with a group of group Q), —N-(lower alkyl which maybe substituted with a group of group Q)₂, —CO-lower alkyl, -loweralkylene-OH, -lower alkylene-hetero ring, -lower alkylene-phenyl,-hetero ring, —CO-hetero ring, —CHO, —CO₂H, —CO₂ lower alkyl, -nitro,—SO-lower alkyl, —SO₂ lower alkyl and —NHCO-(lower alkyl which may besubstituted with a group of group Q). In this connection, hetero ringand phenyl may be substituted with -lower alkyl, -halogen or —OH.

The substituent in the “lower alkyl which may have a substituent(s)” isa group which may be used as a substituent(s) of these rings, and ispreferably a group selected from the following group Q.

Group Q: —OH, —O-lower alkyl, —S-lower alkyl, —NH₂, —NH-lower alkyl,—N(lower alkyl)₂, —CO₂H, —CONH₂, -aryl and -hetero ring. In thisconnection, aryl may be substituted with -lower alkyl, -halogen or —OH,and hetero ring may be substituted with -lower alkyl, —OH or oxo.

Preferred compound among the compound (I) useful as the activeingredient of the present invention is a compound represented by theformula (Ia), formula (Ib) or formula (Ic), and in the other preferredembodiment, R³ and R⁴ together form *—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—,*—N(R⁷)—(CH₂)₃—, *—(CH₂)₃—N(R⁷)—, *—CH₂—N(R⁷)—(CH₂)₂— or*—(CH₂)₂—N(R⁷)—CH₂—. In this case, preferred as R⁷ is H, methyl oracetyl.

Preferred embodiment of the compound (Ia) is shown in the following:

A¹ is preferably CH, C-halogen, C—(O-lower alkyl) or N, more preferablyCH, C-halogen or C—(O-lower alkyl), further preferably CH or C-halogen,most preferably CH.

R³ is preferably —R⁰, -lower alkyl substituted with halogen, -halogen,—OR⁰, -saturated hetero ring, -lower alkylene-heteroaryl or -loweralkylene-saturated hetero ring, more preferably —H, -halogen, —OH,—O—C₁₋₃ alkyl or -lower alkylene-saturated hetero ring, furtherpreferably —H, —Cl, —F or —Br, wherein said saturated hetero ring may besubstituted with 1 to 5 of lower alkyl, OH, O-lower alkyl or oxo.

R⁴ is preferably —X^(a)-saturated hetero ring;

-   -   wherein X^(a) is preferably single bond, —O—, —CO—, —S—, —SO₂—,        —N(R⁰)CO—, -lower alkylene-O—, -lower alkylene-N(R⁰)— or -lower        alkylene-N(R⁰)CO—, more preferably single bond, —O—, —CO—, —S—,        —N(R⁰)−, —N(R⁰)CO— or -lower alkylene-N(R⁰)CO—;        more preferred is —O-piperidyl, —O-pyrrolidyl, —O-quinuclidinyl,        —O-tetrahydrofuranyl, —O-tetrahydropyranyl, —CO-morpholinyl,        —CO-piperidyl, —CO-piperazinyl, —S-tetrahydrofuranyl,        —SO₂-piperidyl, —SO₂-piperazinyl, —C₁₋₄        alkylene-N(Me)-piperidyl, —C₁₋₄        alkylene-N(Me)-tetrahydropyranyl, —C₁₋₄ alkylene-pyrrolidyl,        —C₁₋₄ alkylene-piperidyl, —C₁₋₄ alkylene-piperazinyl, —C₁₋₄        alkylene-morpholinyl, —C₁₋₄ alkylene-thiomorpholinyl, —O—C₁₋₄        alkylene-pyrrolidyl, —O—C₁₋₄ alkylene-piperidyl, —O—C₁₋₄        alkylene-piperazinyl, —O—C₁₋₄ alkylene-morpholinyl, —O—C₁₋₄        alkylene-thiomorpholinyl, -piperidyl, -morpholinyl,        -thiomorpholinyl, homomorpholinyl,        2,5-diazabicyclo[2,2,1]heptyl, -piperazinyl or homopiperazinyl.        In this case, ethylene or dimethylethylene is particularly        desirable as the C₁₋₄ alkylene. In addition, the aforementioned        hetero ring including piperidyl, piperazinyl, homopiperazinyl,        morpholinyl, thiomorpholinyl, pyrrolidyl, tetrahydrofuranyl and        tetrahydropyranyl may be substituted with lower alkyl, OH,        O-lower alkyl, —CO-lower alkylene-N(lower alkyl)₂, lower        alkylene-NHCO-lower alkylene-N(lower alkyl)₂, -lower        alkylene-N(lower alkyl)₂, lower alkylene-CO₂H, —CO₂H, lower        alkylene-CO₂-lower alkyl, —CO₂-lower alkyl, lower        alkylene-CONH₂, —CONH₂, lower alkylene-HNCONH₂, lower        alkylene-NH—SO₂ lower alkyl, lower alkylene-N(lower alkyl)-SO₂        lower alkyl, -lower alkylene-OH or oxo.

B is preferably phenyl, indolyl, indazolyl, furyl or thienyl, and saidphenyl, indolyl, indazolyl, furyl and thienyl may have a substituent(s)selected from the aforementioned group P.

Regarding R¹ and R², preferred is a case in which R¹ is H and R² is H orlower alkyl which may have a substituents) selected from theaforementioned group Q, more preferred is a case in which both of R¹ andR² are H.

Accordingly, as the compound (Ia), a compound consisting of acombination of the aforementioned preferred groups is more desirable.

Preferred embodiment of the compound (Ib) is shown in the following:

A¹ is preferably CH, C-halogen, C—(O-lower alkyl) or N. More preferablyCH or C-halogen, and most preferably CH.

R³ is preferably -saturated hetero ring, —O-saturated hetero ring,—N(R⁰)-saturated hetero ring or -lower alkylene-saturated hetero ring,more preferably -lower alkylene-saturated hetero ring including nitrogenatom, wherein said saturated hetero ring including nitrogen atom may beunsubstituted or substituted with 1 to 5 of lower alkyl, OH, O-loweralkyl or oxo.

R⁴ is preferably —H, —OH, —NH—CHO, —CON(R⁰)₂, -lower alkylenesubstituted with halogen-OH, -lower alkylene-NH₂, -loweralkylene-NHCONH₂, -lower alkylene-CO₂H, -lower alkylene-CO₂-lower alkyl,-lower alkylene-CN, or —CH(lower alkylene-OH)₂, or a group representedby a formula —X^(a)—R^(4a),

wherein preferred as X^(a) is single bond, —O—, —CO—, —S—, —SO₂—,—N(R⁰)CO—, -lower alkylene-O—, -lower alkylene-N(R⁰)— or -loweralkylene-N(R⁰)CO—, and more preferred is single bond, —O—, —CO—,—N(R⁰)—, —N(R⁰)CO— or -lower alkylene-N—(R⁰)CO—;

more preferred is —OH, —CON(R⁰)₂, -lower alkylene substituted withhalogen-OH, -lower alkylene-CN or —CH(lower alkylene-OH)₂, or a grouprepresented by a formula —X^(a)—R^(4a), further preferred is —CH (loweralkylene-OH)₂ or a group represented by the formula —X^(a)—R^(4a) andmost preferred is —OH, —C₁₋₄ alkylene-OH, —CH₂N(Me)₂, —C₁₋₄alkylene-N(Me)—C₅₋₆ cycloalkyl or —CH(CH₂OH)₂. In this case, ethylene ordimethylethylene is particularly desirable as the C₁₋₄ alkylene. Inaddition, the aforementioned cycloalkyl may be substituted with loweralkyl, OH, O-lower alkyl or —N(lower alkyl)₂.

B is preferably phenyl, indolyl, indazolyl, furyl or thienyl, and saidphenyl, indolyl, indazolyl, furyl and thienyl may have a substituentselected from the aforementioned group P.

Regarding R¹ and R², preferred is a case in which R¹ is H and R² is H orlower alkyl which may have a substituent selected from theaforementioned group Q, more preferred is a case in which both of R¹ andR² are H.

Accordingly, as the compound (Ib), a compound consisting of acombination of the aforementioned preferred groups is more desirable.

Preferred embodiment of the compound (Ic) is shown in the following:

R⁵ is preferably —H, —Cl, —F or —Br, more preferably —H or —Cl.

B is preferably H, C₁₋₆ alkyl substituted with halogen, aryl which mayhave a substituent(s), cycloalkyl which may have a substituents) orhetero ring which may have a substituent(s), more preferably phenyl,C₃₋₈ cycloalkyl, indolyl, indazolyl, furyl, thienyl, adamantyl,norbornyl or tetrahydrofuranyl, and said phenyl, indolyl, indazolyl,furyl and thienyl may have a substituent(s) selected from theaforementioned group P, and the C₃₋₈ cycloalkyl may have asubstituent(s) selected from the aforementioned group G.

Y is preferably single bond, or a lower alkylene group which may besubstituted with OH or O—C₁₋₂ alkyl, more preferably single bond or aC₁₋₆ alkylene group. Further preferred is single bond, methylene,methylmethylene or ethylene. Alternatively, in case that B is H,preferred as Y-B is 2-propyl, 2-methylpropyl, tert-butyl,2,2-dimethylpropyl or 3-methylbutyl.

Preferable R¹ and R² include those in which R¹ is H and R² is H or loweralkyl which may have a substituent(s) selected from the aforementionedgroup Q, more preferably, those in which both of R¹ and R² are H.

Accordingly, as the compound (Ic), a compound consisting of acombination of the aforementioned preferred groups is more desirable.

Particularly desirable compounds regarding the compound 1) are thefollowing compounds:4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,2-[(4-morpholin-4-ylphenyl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,4-[(2,6-difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,4-[(2,5-difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,4-[(2-methoxybenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,4-[(2-fluoro-6-methoxybenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,2-({4-[(1-methylpiperidin-3-yl)oxy]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-({4-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-{[4-(2-morpholin-4-ylethoxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-{[4-(β-D-glucopyranosyloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,4-benzylamino-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide,4-benzylamino-2-{[2-(3,5-dichloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide,2-[(4-morpholin-4-ylphenyl)amino]-4-[(2-thienylmethyl)amino]pyrimidine-5-carboxamide,4-{[(3-chloro-2-thienyl)methyl]amino}-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamideand2-{[3-(2-morpholin-4-ylethyl)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide.

The compound (I) and novel compounds (Ia), (Ib) and (Ic) (“compound (I)”hereinafter) useful as the active ingredient of the present inventionmay exist in the form of geometrical isomers and tautomers depending onthe kind of substituents, and their separated forms or mixtures are alsoincluded in the present invention. Also, since the compound (I) hasasymmetric carbon atom in some cases, isomers based on the asymmetriccarbon atom may be present. Mixtures and isolated forms of these opticalisomers are included in the present invention. In addition, compoundsprepared by labeling the compound (I) with radioisotopes are included inthe present invention.

In some cases, the compound (I) forms an acid addition salt or,depending on the kind of substituents, a salt with a base, and suchsalts are included in the present invention with the proviso that theyare pharmaceutically acceptable salts. Their illustrative examplesinclude acid addition salts with inorganic acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,phosphoric acid and the like and with organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid,glutamic acid and the like, salts with inorganic bases such as sodium,potassium, magnesium, calcium, aluminum and the like or with organicbases such as methylamine, ethylamine, ethanolamine, lysine, ornithineand the like, ammonium salts and the like. Further, the presentinvention also includes various hydrates, solvates and polymorphicsubstances of the compound (I) and its pharmaceutically acceptablesalts.

In addition, a pharmacologically acceptable prodrug is also included inthe present invention. The pharmacologically acceptable prodrug is acompound having the group of the present invention which may beconverted into NH₂, OH, CO₂H or the like by solvolysis or underphysiological conditions. As the groups which can form prodrugs, thegroups described in Prog. Med., 5, 2157-2161 (1985) and “Iyakuhin-noKaihatsu (Development of Medicaments)” (written in Japanese, HirokawaShoten) vol. 7 Bunshi Sekkei (Molecular Design) 163-198 may beexemplified.

(Production Methods)

The compound (I) or a pharmaceutically acceptable salt thereof may beproduced by employing various conventionally known synthesis methods,making use of the characteristics based on its basic skeleton or thekind of substituents. In that case, depending on the kind of functionalgroup, there is a case in which it is effective from a productiontechnical point of view to protect said functional group or replace itby a group which may be easily converted into said functional group at astage of the material or an intermediate. Examples of such a functionalgroup include amino group, hydroxyl group, carboxyl group and the like,examples of their protecting groups include the protecting groupsdescribed in “Protective Groups in Organic Synthesis (3rd edition,1999)” edited by Greene (T. W. Greene) and Wuts (P. G. M. Wuts), andthese may be optionally selected and used in response to the reactionconditions. In such a method, a desired compound may be obtained byintroducing said protecting group and carrying out the reaction, andthen removing the protecting group as occasion demands, or converting itinto a desired group. In addition, a prodrug of the compound (I) may beproduced by introducing a specified group at a stage of the material oran intermediate similar to the case of the aforementioned protectinggroup, or carrying out a reaction using the obtained compound (I). Thereaction may be carried out by employing a conventional method known tothose skilled in the art such as general esterification, amidation,carbamation, dehydration or the like.

The following describes typical production methods of the compounds ofthe present invention regarding the compound of formula (I), and thecompounds of formulae (Ia), (Ib) and (Ic) can also be produced in thesame manner.

Production Method A Substitution Reaction (1)

(In the formula, L¹ represents a leaving group. The same shall applyhereinafter.)

This production method is a method in which the compound (I) is obtainedby allowing a pyrimidine compound (II) to react with an amine compound(III). In this case, examples of the leaving group of L¹ include ahalogen atom, methylsulfanyl, methylsulfinyl, methylsulfonyl,1H-benzotriazol-1-yloxy, methylsulfonyloxy, p-toluenesulfonyloxy;trifluoromethanesulfonyloxy and the like.

The reaction may be carried out without solvent or in a solvent inert tothe reaction such as aromatic hydrocarbon (e.g., benzene, toluene,xylene or the like), ether (e.g., diethyl ether, tetrahydrofuran (THF),dioxane or the like), halogenated hydrocarbon (e.g., dichloromethane,1,2-dichloroethane, chloroform or the like), N,N-dimethylformamide(DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ethylacetate, acetonitrile or the like, using the compounds (II) and (III) inequimolar basis or one of them in an excess amount, and at roomtemperature to under heat reflux. The reaction temperature may beoptionally set in accordance with the compounds. Depending on thecompounds, it is sometimes advantageous to carry out the reaction in thepresence of an organic base (preferably diisopropylethylamine,N-methylmorpholine, pyridine or 4-(N,N-dimethylamino)pyridine) or ametal base (preferably potassium carbonate or sodium hydroxide). Also,depending on the compounds, it is sometimes advantageous to carry outthe reaction under an acidic condition (in the presence of 4 M hydrogenchloride/1,4-dioxane solution, 4 M hydrogen chloride/ethyl acetatesolution or the like) or in the presence of a fluoride ion (potassiumfluoride, cesium fluoride, tetrabutylammonium fluoride or the like).

In this connection, in case that the compound (I) has a primary orsecondary amino group, it may be produced by protecting amino groups ofthe compound (II) and compound (III) as the material compounds inadvance with a protecting group, carrying out said substitution reactionand then removing the protecting group. The protecting group may beoptionally selected from the protecting groups described in theaforementioned “Protective Groups in Organic Synthesis”.

Production Method B Substitution Reaction (2)

(In the formula, L² represents a leaving group. The same shall applyhereinafter.)

This production method is a method in which the compound (I) is obtainedby allowing a pyrimidine compound (IV) to react with an amine compound(V), and it may be produced in the same manner as the method describedin the aforementioned Production Method A. In this case, a group similarto the aforementioned leaving group L¹ may be used as the leaving groupL².

Production Method C Amidation Reaction

This production method is a method in which the compound (I) is obtainedthrough the amidation of a carboxylic acid derivative (VI).

A free carboxylic acid or a reactive derivative thereof may be used inthis reaction as the carboxylic acid derivative (VI), and examples ofsaid reactive derivative include acid halides (acid chloride, acidbromide and the like), acid anhydrides (mixed anhydride obtained by thereaction with ethyl chlorocarbonate, benzyl chlorocarbonate, phenylchlorocarbonate, p-toluenesulfonic acid, isovaleric acid and the like,or symmetric acid anhydrides), activated esters (esters which may beprepared using phenol, 1-hydroxybenzotriazole (HOBt),N-hydroxysuccinimide (HONSu) or the like that may be substituted with anelectron withdrawing group such as a nitro group, a fluorine atom or thelike), a lower alkyl ester, an acid azide and the like. These reactivederivatives may be produced in the usual way.

When a free carboxylic acid is used, it is desirable to use a condensingagent (such as (N,N′-dicyclohexylcarbodiimide (DCC),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC),1,1′-carbonylbisimidazole (CDI), N,N′-disuccinimidyl-carbonate, Bopreagent (Aldrich, USA),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), diphenyl phosphate azide (DPPA), phosphorus oxychloride,phosphorus trichloride, triphenylphosphine/N-bromosuccinimide or thelike), further using an additive agent (e.g., HONSu, HOBt or the like)as occasion demands.

The reaction is carried out using the carboxylic acid derivative (VI)and an amine (VII) in equimolar basis or one of them in an excessamount, in an inert solvent such as an aromatic hydrocarbon, ahalogenated hydrocarbon, an ether, DMF, DMA, NMP, ethyl acetate,acetonitrile or the like, under cooling to heating, preferably from −20°C. to 60° C. Depending on the kind of reactive derivatives, it issometimes advantageous in effecting smooth progress of the reaction tocarry out the reaction in the presence of a base (preferablytriethylamine, disopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine or the like). Pyridine can also serve asthe solvent.

Production Method D Solid Phase Synthesis

(In the formula, Res represents a resin for solid phase synthesis. Thesame shall apply hereinafter.)

This production method is a method producing by a solid phase synthesismethod which consists of the following three steps.

(1) Fixation to a Resin (Amidation)

A carboxylic acid compound (VIII) and a resin for solid phase synthesisuse having amino termini (e.g., an amino(methyl) resin, Rink amide resinor the like) are condensed in the same manner as in the aforementionedProduction Method C.

(2) Substitution Reaction

The production is effected by carrying out a substitution reaction inthe same manner as in Production Method A using the amine compound(III).

(3) Removal of the Resin

A compound (I′) is produced by eliminating the resin from a compound(X). The reaction is carried out without solvent or in a solvent inertto the reaction (e.g., an aromatic hydrocarbon, an ether, a halogenatedhydrocarbon, an alcohol, DMF, DMA, NMP, pyridine, dimethyl sulfoxide(DMSO), ethyl acetate, acetonitrile or the like), by treating with amineral acid (e.g., hydrochloric acid, hydrobromic acid or the like) oran organic acid (e.g., trifluoroacetic acid or the like). It isadvantageous in some cases to catty out the reaction in the presence ofadditive agent (e.g., difluoroethanol, triethylsilane,triisopropylsilane, (thio)anisole or the like).

Production Method E Other Production Methods

The compounds of the present invention having various functional groupssuch as amido group, ureido group, alkylamino group and the like canalso be produced by using the compounds of the present invention havingcorresponding amino group and the like as the materials and employing amethod obvious to those skilled in the art, a conventionally knownproduction method or a modified method thereof. For example, thefollowing reactions may be employed.

E-1: Amidation

Various amide compounds may be produced by allowing various carboxylicacid compounds or reactive derivatives thereof to react with a compoundof the present invention having amino group. The aforementioned methodProduction Method C may be employed in this reaction. In addition,various sulfonamide derivatives may be produced by the use of varioussulfonic acid derivatives (reactive derivatives such as sulfonic acidhalides, sulfonic acid anhydrides and the like are desirable) instead ofthe carboxylic acid compounds.

E-2: Ureation

They may be produced by allowing ureation agents such as a cyanic acidderivative (e.g., sodium cyanate, potassium cyanate or the like), anisocyanate derivative, urea, cyanogen bromide and the like to react withthe compounds of the present invention having amino group, withoutsolvent or in an solvent inert to the reaction (e.g., an aromatichydrocarbon, an ether, a halogenated hydrocarbon, an alcohol, water,DMF, DMA, NMP, pyridine, DMSO, ethyl acetate, acetonitrile or the like).These solvents may be used alone or as a mixture of two or more. It issometimes advantageous in effecting smooth progress of the reaction tocarry out the reaction in the presence of an acid (e.g., acetic acid,hydrochloric acid or the like) or a base (e.g., sodium hydroxide,potassium hydroxide or the like). The reaction may be carried out undercooling to heating reflux, and the reaction temperature may beoptionally set depending on the compound.

E-3: Alkylation (1)

Alkyl groups may be introduced by allowing compounds having amino groupto react with various alkylating agents (e.g., alkyl-halides, sulfonicacid esters and the like) in the usual way. In addition, in case that asecondary amine is produced from a primary amine, a method in which amaterial is once made into a trifluoroacetylamino form, alkylated andthen hydrolyzed (Tetrahedron Letters, 1978, 4987 and the like) may beemployed.

E-4 Alkylation (2)

Alkylated compounds may be produced by subjecting compounds having aminogroup to a reductive alkylation with various carbonyl compounds. Thereaction may be carried out by employing a method described, forexample, in “Jikken Kagaku Koza (Experimental Chemistry Course)(Maruzen)” edited by The Chemical Society of Japan (4th edition, vol.20, 1992, 300).

E-5: Oxidation

Oxide compounds may be obtained by treating compounds having tertiaryamino groups or nitrogen-containing aromatic rings (e.g., pyridine andthe like) with various oxidizing agents. The reaction may be carried outby employing a method described, for example, in “Jikken Kagaku Koza(Maruzen)” edited by The Chemical Society of Japan (4th edition, vol.23, 1991, 271).

E-6: Reduction

A compound having amino group may be produced by subjecting a compoundhaving oxidoamino group to a reductive treatment (e.g., reaction withsodium hydrogen sulfite or the like).

Production Method F Production Method of Material Compounds

Material compounds to be used in the production of the compound (I) maybe produced in the usual way, for example, using conventionally knownreactions shown in the following synthesis pathway.

In the above reaction scheme, the substitution reaction may be carriedout in the same manner as in the aforementioned Production Method A orB, and the amidation in the same manner as in the aforementionedProduction Method C, respectively. The carboxyl group deprotectioncondition described in the aforementioned “Protective Groups in OrganicSynthesis” may be applied to the hydrolysis, and other alkyl ester,benzyl ester and the like can also be used instead of the ethyl ester.

The reaction products obtained by the aforementioned respectiveproduction methods may be isolated and purified as free compounds, saltsthereof or various solvates such as hydrate and the like. The salts maybe produced by subjecting to general salt forming treatments.

Isolation and purification may be carried out by employing generalchemical operations such as extraction, concentration, evaporation,crystallization, filtration, recrystallization, various types ofchromatography and the like.

Various types of isomers may be isolated in the usual way making use ofa physicochemical difference between isomers. For example, opticalisomers may be separated by a general optical resolution method such asfractional crystallization or chromatography. In addition, opticalisomers can also be produced from an appropriate optically activematerial compound.

INDUSTRIAL APPLICABILITY

As is also confirmed by the following Examples, the compound (I) usefulas the active ingredient of the present invention has superiorinhibitory activity for STAT 6 activation and is useful as an agent forpreventing or treating respiratory diseases (asthma, CODP and the like)and allergic diseases (rhinitis, dermatitis and the like), in which STAT6 is concerned.

In addition, since the compound (I) has the potent inhibitory activityfor STAT 6 activation in comparison with the inhibitory activity forimmunocyte activation by an antigen receptor stimulation and havecompounds having a selectivity of 100 times or more, it is useful as theaforementioned preventive or therapeutic agent having less action uponthe immunosuppression function. In this connection, the immunocyteactivation inhibition by an antigen receptor stimulation may beevaluated, for example, based on the inhibition of intracellular calciumconcentration increase in a B cell strain (RAMOS cell) by anti-IgMantibody stimulation and the inhibition of IL-2 production from a mousespleen-derived T cell by anti-CD3 antibody stimulation.

The pharmaceutical preparation which contains one or two or more of thecompounds (I) or salts thereof as the active ingredient is preparedusing a carrier, a filler and other additives generally used inpreparing medicaments:

Its administration may be in the form of either oral administrationthrough tablets, pills, capsules, granules, powders, solutions and thelike, or parenteral administration through injections such asintravenous injections, intramuscular injections or the like,suppositories, percutaneous preparations, transnasal preparations,inhalations and the like. The dose is optionally decided in response toeach case, by taking into consideration symptoms, age, sex and the likeof each subject to be administered, but is generally from 0.001 mg/kg to100 mg/kg per day per adult in the case of oral administration, and thisis administered once a day or by dividing into 2 to 4 daily doses, or iswithin the range of from 0.0001 mg/kg to 10 mg/kg per day per adult inthe case of intravenous injection and this is administered once a day ordividing into two or more daily doses. In addition, in the case oftransnasal administration, this is administered generally within therange of from 0.0001 mg/kg to 10 mg/kg per day per adult, once a day ordividing into two or more daily doses, and in the case of inhalation,this is administered generally within the range of from 0.0001 mg/kg to1 mg/kg per day per adult, once a day or dividing into two or more dailydoses.

As a solid composition of the present invention for oral administration,tablets, powders, granules and the like are used. In such a solidcomposition, one or more active substances are mixed with at least oneinert excipient such as lactose, mannitol, glucose,hydroxypropylcellulose, microcrystalline-cellulose, starch, polyvinylpyrrolidone, aluminum magnesium silicate or the like. In the usual way,this composition may contain inactive additives such as a lubricant(e.g., magnesium stearate or the like), a disintegrating agent (e.g.,carboxymethylstarch sodium or the like), and a solubilization assistingagent. As occasion demands, tablets or pills may be coated with a sugarcoating or a film of a gastric or enteric coating agent.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs and thelike and contains a generally used inert solvent such as purified wateror ethanol. In addition to the inert solvent, this composition maycontain auxiliary agents such as a solubilizing agent, a moisteningagent and a suspending agent, as well as a sweetener, a correctives, anaromatic or an antiseptic.

The injections for parenteral administration includes aseptic aqueous ornon-aqueous solutions, suspensions and emulsions. The aqueous solventincludes, for example, distilled water for injection and physiologicalsaline. The non-aqueous solvent includes, for example, propylene glycol,polyethylene glycol, plant oil (e.g., olive oil or the like), alcohol(e.g., ethanol or the like), polysorbate 80 (trade name) and the like.Such a composition may further contain a tonicity agent, an antiseptic,a moistening agent, an emulsifying agent, a dispersing agent, astabilizing agent, a solubilization assisting agent and the like. Theseare sterilized, for example, by filtration through a bacteria retainingfilter, blending of a germicide or irradiation. Alternatively, a sterilesolid composition is produced, which may be used by dissolving orsuspending in sterile water or other sterile solvent for injection priorto its use.

In the case of inhalations and transmucosal preparations such astransnasal preparations, those in the solid, liquid or semi-solid stateare used, and they may be produced in accordance with conventionallyknown methods. For example, excipients (e.g., lactose, starch and thelike), and also a pH adjusting agent, an antiseptic, a surfactant, alubricant, a stabilizer, a thickener and the like, may be optionallyadded. An appropriate device for inhalation and exhalation may be usedfor the administration. For example, using a conventionally known deviceor sprayer such as a measuring administration inhalation device, acompound may be administered alone or as a powder of a prescribedmixture, or as a solution or suspension in combination with apharmaceutically acceptable carrier. A dry powder inhalation device orthe like may be for a single or multiple administration use, and a drypowder or powder-containing capsules may be used Alternatively, it maybe a pressure aerosol sprayer type or the like which uses an appropriatepropellant such as chlorofluoroalkane, hydrofluroalkane or carbondioxide or the like appropriate gas.

BEST MODE FOR CARRYING OUT THE INVENTION

The following illustratively describes the present invention based onExamples, but these do not limit the scope of the present invention.Production methods of the material compounds are shown in ReferenceExamples. In addition, production methods of compounds which areincluded in the formula (I) but not included in the formula (Ia), (Ib)or (Ic) are shown in Production Examples.

The following abbreviations are used in the Reference Examples and thetables which are shown later. Rex: reference example number, Pre:production example number, Ex: example number, Cmpd: compound number,Str: structural formula, Syn: production method (the figures showexample or production example numbers produced in the same manner), Me:methyl, Et: ethyl, Pr: 1-propyl, iPr: 2-propyl, Bu: butyl, tBu:tert-butyl, Boc: tBu-O—CO—, Ac: acetyl, Ms, Me-SO₂—, Ph: phenyl, Bn:benzyl, Bz: benzoyl, cPr: cyclopropyl, cBu: cyclobutyl, cPen:cyclopentyl, cHex: cyclohexyl, cHep: cycloheptyl, cOct: cyclooctyl, 2Ad:2-adamantyl, 2Py: 2-pyridyl, 3Py: 3-pyridyl, 4Py: 4-pyridyl, 3Qui:3-quinolyl-, Dat: physicochemical date(F: FAB-MS (M+H)⁺; FN: FAB-MS(M−H)⁻; ESI: ESI-MS (+H)⁺; EI: EI-MS (++H)⁺; NMR1: δ (ppm) ofcharacteristic peak of ¹H NMR in DMSO-d₆; NMR2: δ (ppm) ofcharacteristic peak of ¹H NMR in CDCl₃; MP: melting point (° C.); Sal:salt (no description: free; HCl: hydrochloride; the numeral shows theratio of acid components, for example, 2 HCl means dihydrochloride)). Inaddition, the number before each substituent indicates the substitutingposition, and the presence of two or more numbers indicates two or moresubstitutions. For example, 2-MeO-Ph indicates 2-methoxyphenyl, and2,4-F₂-Ph indicates 2,4-difluorophenyl.

Reference Example 1

A Boc compound obtained by allowing 4-(2-aminoethyl)aniline to reactwith tert-butyl dicarbonate in THF was allowed to react with formic acidin dichloromethane in the presence of WSC hydrochloride, therebyobtaining a formylaminophenyl compound. This was further treated with 4M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain4-(2-aminoethyl)phenylformamide hydrochloride. F: 165.

Reference Example 2

3-(2-morpholin-4-ylethyl)aniline was obtained by treating3-(2-morpholin-4-yl-2-oxoethyl)aniline with lithium aluminum hydride inTHF. F: 207.

Reference Example 3

A compound obtained by allowing 4-nitrobenzyl bromide and2-(morpholin-4-yl)ethylamine to undergo the reaction in DMF in thepresence of potassium carbonate was allowed to react with di-tert-butylcarbonate in 1,4-dioxane, thereby obtaining a Boc compound. This wasfurther subjected to catalytic hydrogenation in methanol in the presenceof 10% palladium/carbon to obtain tert-butyl4-aminobenzyl-(2-morpholin-4-ylethyl)carbamate. F: 336.

Reference Example 4

In the presence of triethylamine, a toluene solution of2-(4-nitrophenyl)propionic acid was allowed to react with DPPA at roomtemperature and then under heating, and further allowed to react withtert-butanol under heating, thereby obtaining a Boc compound (F: 366).The resulting compound was subjected to catalytic hydrogenation in thesame manner as shown in Reference Example 3 to obtain tert-butyl1-(4-aminophenyl)ethylcarbamate. NMR1: 1.23 (3H, d, J=8.8 Hz), 1.35 (9H,s), 6.48 (2H, d, J=8.4 Hz).

Reference Example 5

4-(4-nitrophenyl)butanoic acid and piperidine were allowed to undergothe reaction in DMF using WSC hydrochloride and HOBt, Subjected tocatalytic hydrogenation in the same manner as shown in Reference Example3 to reduce the nitro group, and then reduced in the same manner as inReference Example 2, and the resulting compound was subjected to saltformation using 4 M hydrogen chloride/ethyl acetate solution to obtain4-(4-piperidin-1-ylbutyl)aniline dihydrochloride. F: 233.

Reference Example 6

N-methylation of N-(4-nitrophenyl)morpholine-4-carboxamide was effectedby allowing it to react with sodium hydride and methyl iodide in DMF,and the resulting compound was subjected to catalytic hydrogenation inthe same manner as shown in Reference Example 3 to obtainN-(4-aminophenyl)-N-methylmorpholine-4-carboxamide. F: 236.

Reference Examples 7 and 8

4-Fluoronitrobenzene and 2,6-dimethylmorpholine were allowed to undergothe reaction in DMF in the presence of diisopropylethylamine, and thencis and trans isomers were separated and purified by a silica gel columnchromatography and respectively subjected to catalytic hydrogenation inthe same manner as shown in Reference Example 3 to obtaincis-4-(2,6-dimethylmorpholin-4-yl)aniline (Reference Example 7; F: 207)and trans-4-(2,6-dimethylmorpholin-4-yl)aniline (Reference Example 8; F:207).

Reference Example 9

2-Fluoro-4-nitrotoluene and p-formaldehyde were allowed to undergo thereaction in DMSO in the presence of sodium methoxide, and then theresulting compound was subjected to catalytic hydrogenation in the samemanner as shown in Reference Example 3 to obtain3-fluoro-4-(2-hydroxyethyl)aniline. F: 156.

Reference Example 10

3,4,5-Trifluorobenzoic acid was allowed to react with ethanol in thepresence of concentrate sulfuric acid and then allowed to react withmorpholine in DMF solution, thereby obtaining3,5-difluoro-(4-morpholin-4-yl)benzoic acid ethyl ester (EI (M⁺): 271).This was further hydrolyzed in methanol with 1 M sodium hydroxideaqueous solution, and then allowed to react with DPPA in toluene in thepresence of triethylamine at room temperature, heated, and furtherallowed to react with tert-butanol under heating, thereby obtaining aBoc compound (F: 315). By further treating with 4 M hydrogenchloride/ethyl acetate solution, 3,5-difluoro-4-(morpholin-4-yl)anilinehydrochloride was obtained. F: 215.

Reference Example 11

2-Chloro-4-{[3-(1-hydroxyethyl)phenyl]amino}pyrimidine-5-carboxylic acidethyl ester synthesized in accordance with the method described in WO99/31073 and 2-(3,5-dichloro-4-hydroxyphenyl)ethylamine hydrochloridewere allowed to undergo the reaction at 80 to 90° C. in NMP in thepresence of diisopropylethylamine, and the resulting compound wasallowed to react with 1 M sodium hydroxide aqueous solution underheating in a mixed methanol-THF solution to obtain2-{[2-(3,5-dichloro-4-hydroxyphenyl)ethyl]amino}-4-([3-(1-hydroxyethyl)phenyl]amino)pyrimidine-5-carboxylicacid. F: 463

Reference Example 12

2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester was allowed toreact with sodium thiomethylate at −10° C. in THF in the presence ofbenzyl triethylammoniumchloride and then allowed to react with tyraminehydrochloride at 70° C. in NMP in the presence of diisopropylethylamine.The resulting compound was hydrolyzed in methanol using 1 M sodiumhydroxide aqueous solution and then treated in NMP with aqueous ammoniain the presence of WSC hydrochloride and HOBt to convert into acarboxamide compound which was further allowed to react withm-chloroperbenzoic acid in NMP, thereby obtaining2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-(methylsulfinyl)pyrimidine-5-carboxamide.F: 321.

Reference Example 13

2-Chloro-4-(methylthio)pyrimidine-5-carboxylic acid ethyl ester wasallowed to react with 4-(morpholin-4-yl)aniline at 90° C. in NMP in thepresence of 4 M hydrogen chloride/dioxane and further treated in thesame manner as in and after the hydrolysis of Reference Example 12 toobtain4-(methylsulfinyl)-2-{[4-(4-oxidomorpholin-4-yl)phenyl]amino}pyrimidine-5-carboxamide.F: 378.

Reference Example 14

4-Chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester andbenzylamine were allowed to undergo the reaction in acetonitrile in thepresence of diisopropylethylamine and further treated in the same manneras in and after the hydrolysis of Reference Example 12 to obtain4-benzylamino-2-(methylsulfonyl)pyrimidine-5-carboxamide. F: 307.

Reference Example 15

2-(Benzotriazol-1-yloxy)-4-([3-(1-hydroxyethyl)phenyl]amino)pyrimidine-5-carboxamidewas synthesized in the same manner as the method of Reference Example 6in WO 99/31073. F: 392.

Reference Example 16

2,4-Dichloropyrimidine-5-carboxylic ethyl ester and m-toluidine wereallowed to undergo the reaction in acetonitrile in the presence ofdiisopropylamine to obtain2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylic ethyl ester.Said ester compound was hydrolyzed in THF with 1 M sodium hydroxideaqueous solution, and the resulting carboxylic acid compound was allowedto react with oxalyl chloride in dichloromethane in the presence of acatalytic amount of DMF and then treated with a mixture of aqueousammonia and ice to obtain2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide. F: 263.

Reference Example 17

2-{[4-(Aminomethyl)phenyl]amino}-N-methyl-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidewas obtained in the same manner as in Production Example 8 which isdescribed later, using2-chloro-N-methyl-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide andtert-butyl(4-aminophenyl)methylcarbamate. F: 363.

Reference Example 18

2-Benzyloxy-6-fluorobenzylamine was obtained by reducing2-benzyloxy-6-fluorobenzamide in the same manner as in Reference Example2. F: 232.

Reference Example 19

4-(2-Morpholin-4-yl-ethoxy)aniline dihydrochloride was obtained bycarrying out catalytic hydrogenation of1-[2-(4-nitrophenoxy)ethyl]morpholine in the same manner as in ReferenceExample 3 and then treating with 4 M hydrogen chloride/ethyl acetate. F:223.

Reference Example 20

1-(4-Nitrophenyl)pyrrolidin-3-ol and methanesulfonyl chloride wereallowed to undergo the reaction in THF in the presence of triethylamine.The resulting compound and sodium cyanide were allowed to undergo thereaction in 1-methyl-2-pyrrolidone under heating. The resulting compoundwas subjected to catalytic hydrogenation in the same manner as shown inReference Example 3 to obtain1-(4-aminophenyl)pyrrolidine-3-carbonitrile. NMR2: 1.48 (9H, s),3.12-3.19 (2H, m), 6.46-6.50 (2H, m).

Reference Example 21

1-(4-nitrophenyl)piperazine and N,N-dimethylglycine hydrochloride wereallowed to undergo the reaction using WSC hydrochloride and HOBt in1-methyl-2-pyrrolidone in the presence of triethylamine. The resultingcompound was subjected to catalytic hydrogenation in the same manner asshown in Reference Example 3 to obtain1-[4-(4-aminophenyl)piperazin-1-yl]-2-dimethylaminoethanone. NMR2: 2.30(6H, s), 3.74-3.76 (4H, m), 6.64-6.68 (2H, m).

Reference Example 22

2-[1-(4-Nitrophenyl)piperidin-4-yl]ethanol and methanesulfonyl chloridewere allowed to undergo the reaction in THF in the presence oftriethylamine. The resulting compound and morpholine were allowed toundergo the reaction under heating in 1-methyl-2-pyrrolidine. Theresulting compound was subjected to catalytic hydrogenation in the samemanner as shown in Reference Example 3 to obtain4-[4-(2-morpholin-4-ylethyl)piperidin-1-yl]aniline. NMR2 (CDCl₃):3.21-3.45 (4H, m), 3.71-3.80 (4H, m), 6.63-6.66 (2H, m).

Reference Example 23

6-(4-Nitrophenyl)morpholin-3-one was treated in the same manner as theN-methylation shown in Reference Example 6, and the resulting compoundwas subjected to catalytic hydrogenation in the same manner as shown inReference Example 3 to obtain 6-(4-aminophenyl)-N-methylmorpholin-3-one.F: 207.

Reference Example 24

6-(4-Aminophenyl)-N-methylmorpholin-3-one was treated in the same manneras the reduction shown in Reference Example 2 and further treated with 4M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain4-(4-methylmorpholin-2-yl)phenylamine dihydrochloride. F: 193.

Reference Example 25

(R)-5-phenylmorpholin-3-one was allowed to react with nitric acid inconcentrated sulfuric acid, and the resulting(R)-5-(4-nitrophenyl)morpholin-3-one (F: 223) was subjected to catalytichydrogenation in the same manner as shown in Reference Example 3 toobtain (R)-5-(4-aminophenyl)morpholin-3-one. F: 193.

Reference Example 26

4-Fluoronitrobenzene and piperidin-4-one hydrochloride were allowed toundergo the reaction in THF in the presence of potassium carbonate. Theresulting compound was allowed to react with sodium hydride and ethyldiethylphosphonoacetate in THF. The resulting compound was subjected tocatalytic hydrogenation in the same manner as shown in Reference Example3 to obtain [1-(4-aminophenyl)piperidin-4-yl]acetic acid ethyl ester.NMR2: 1.27 (3H, t, J=7.2 Hz), 2.33 (2H, d, J=7.2 Hz), 6.66-6.89 (2H, m).

Reference Example 27

(R)-5-(4-nitrophenyl)morpholin-3-one was treated with borane-THF in THF,and the resulting compound was allowed to react with di-tert-butyldicarbonate in dichloromethane to obtain a Boc compound (F: 309) whichwas subsequently subjected to catalytic hydrogenation in the same manneras shown in Reference Example 3 to obtain(R)-3-(4-aminophenyl)morpholine-4-carboxylic acid tert-butyl ester. F:279.

Reference Example 28

2-[1-(4-Nitrophenyl)piperidin-4-yl]ethanol and methane sulfonyl chloridewere allowed to undergo the reaction in THF in the presence oftriethylamine. The resulting compound and potassium phthalimide wereallowed to undergo the reaction under heating in 1-methyl-2-pyrrolidonein the presence of potassium iodide. The resulting compound was allowedto react with hydrazine monohydrate in chloroform-methanol. Theresulting compound and di-tert-butyl dicarbonate were allowed to undergothe reaction under heating in THF. The resulting compound was subjectedto catalytic hydrogenation in the same manner as shown in ReferenceExample 3 to obtain tert-butyl{2-[1-(4-aminophenyl)-piperidin-4-yl]ethyl}-carbamate. FN: 318.

Reference Example 29

1-(4-Nitrophenyl)piperazine and N-(3-bromopropyl)phthalimide wereallowed to undergo the reaction under heating in 1-methyl-2-pyrrolidonein the presence of potassium carbonate. The resulting compound wasallowed to react with hydrazine monohydrate in THF. The resultingcompound and di-tert-butyl dicarbonate were allowed to undergo thereaction in THF. The resulting compound was subjected to catalytichydrogenation in the same manner as shown in Reference Example 3 toobtain tert-butyl {3-[4-(4-aminophenyl)-piperazin-1-yl]propyl}carbamate.F: 335.

Reference Example 30

1-(4-Nitrophenyl)piperazine and ethyl 4-bromobutanoate were allowed toundergo the reaction under heating in 1-methyl-2-pyrrolidone in thepresence of potassium carbonate. The resulting compound was subjected tocatalytic hydrogenation in the same manner as shown in Reference Example3 to obtain ethyl 4-[4-(4-aminophenyl)-piperazin-1-yl]butanoate. F: 264.

Reference Example 31

4-Fluoronitrobenzene and morpholine-3-carboxylic acid ethyl ester wereallowed to undergo the reaction at 100° C. in DMSO in the presence ofdiisopropylethylamine, and then the resulting compound was subjected tocatalytic hydrogenation the same manner as shown in Reference Example 3to obtain 4-(4-aminophenyl)morpholine-3-carboxylic acid ethyl ester.ESI: 251.

Reference Example 32

1-(4-Nitrophenyl)piperazine and 4-bromobutyronitrile were allowed toundergo the reaction under heating in 1-methyl-2-pyrrolidone in thepresence of potassium carbonate. The resulting compound was allowed toreact with polyphosphoric acid under heating and then subjected tocatalytic hydrogenation in the same manner as shown in Reference Example3 to obtain 4-[4-(4-aminophenyl)piperazin-1-yl]butanamide. F: 263.

Reference Example 33

4-Fluoronitrobenzene and 1-methylpyrrolidin-3-ol were allowed to undergothe reaction in 1-methylpyrrolidone in the presence of sodium hydride.The resulting compound was subjected to catalytic hydrogenation in thesame manner as shown in Reference Example 3 to obtain4-(1-methylpyrrolidin-3-yl)oxoaniline. F: 193.

Reference Example 34

1-(4-Nitrophenyl)piperazine and N-(3-bromopropyl)phthalimide wereallowed to undergo the reaction under heating in 1-methyl-2-pyrrolidonein the presence of potassium carbonate. The resulting compound wasallowed to react with hydrazine monohydrate in THF. The resultingcompound was allowed to react with trimethylsilyl isocyanate in THF andthen subjected to catalytic hydrogenation in the same manner as inReference Example 3 to obtain{3-[4-(4-aminophenyl)piperazin-1-yl]propyl}urea. F: 276.

Reference Example 35

3-Fluoronitrobenzene and 2-morpholin-4-yl ethylamine were added, and theresulting compound was subjected to catalytic hydrogenation in the samemanner as shown in Reference Example 3 and then treated with 4 Mhydrogen chloride/ethyl acetate solution in ethyl acetate to obtain3-[N-(2-morpholin-4-ylethyl)amino]aniline hydrochloride. F: 222.

Reference Example 36

2-Morpholin-4-yl-5-nitrophenol and 4-(2-chloroethyl)morpholine wereallowed to undergo the reaction in DMF in the presence of potassiumcarbonate, and then the resulting compound was subjected to catalytichydrogenation in the same manner as shown in Reference Example 3 andfurther treated with 4 M hydrogen chloride/ethyl acetate solution inethyl acetate to obtain 4-morpholin-4-yl-3-(2-morpholin-4-ylethoxy)aniline hydrochloride. F: 308.

Reference Example 37

6-Hydroxy-2-methyl-3,4-dihydro-2H-Isoquinolin-1-one was allowed to reactwith trifluoromethanesulfonic anhydride in dichloromethane in thepresence of 2,6-lutidine and dimethylaminopyridine, and the resultingcompound was introduced with carbon monoxide gas in a mixture ofmethanol, DMF, triethylamine, palladium acetate and1,3-bis(diphenylphosphino)propane to obtain a methyl ester compound (F:220). Subsequently, this was hydrolyzed in methanol with 1 M sodiumhydroxide aqueous solution, allowed to react with DPPA at roomtemperature in toluene in the presence of triethylamine, heated, andthen allowed to react with tart-butanol under heating to obtain a Boccompound (F: 277). This was further treated with 4 M hydrogenchloride/ethyl acetate solution to obtain6-amino-2-methyl-3,4-dihydro-2H-Isoquinolin-1-one hydrochloride. EI:176.

Reference Example 38

2-Methyl-2H-Isoquinolin-1-one was subjected to catalytic hydrogenationin a hydrogen atmosphere in ethanol in the presence of palladium/carbon.The resulting compound and concentrated nitric acid were allowed toundergo the reaction in concentrated sulfuric acid. The resultingcompound was subjected to catalytic hydrogenation in the same manner asshown in Reference Example 3 to obtain7-amino-2-methyl-3,4-dihydro-2H-isoquinolin-1-one. NMR2: 2.88 (2H, t,J=6.8 Hz), 3.13 (3H, s), 6.95 (1H, d, J=8.0 Hz).

Reference Example 39

2-Methoxy-5-methylbenzamide was treated in the same manner as thereduction shown in Reference Example 2 and further treated with 4 Mhydrogen chloride/ethyl acetate solution to obtain2-methoxy-5-methylbenzylamine. F: 152.

Reference Example 40

2-Fluoro-5-formylbenzonitrile was treated with sodium borohydride anddimethyl sulfate in THF to obtain 5-hydroxymethyl-2-fluorobenzylamine.F: 156.

Reference Example 41

2,6-Dimethoxybenzylamine was treated with 48% hydrobromic acid to obtain2,6-dihydroxybenzylamine hydrobromide. F: 140.

Reference Example 42

By treating 3-fluorobenzonitrile with N-methylethanolamine underheating, 3-(N-2-hydroxyethyl-N-methylamino)benzonitrile was obtained (F:177). This benzonitrile was treated in the same manner as in ReferenceExample 2 to obtain 3-(N-2-hydroxyethyl-N-methylamino)benzylamine. F:181.

Reference Example 43

4-Nitrocinnamic acid and 1-methylpiperidine were condensed in the samemanner as the amidation shown in Reference Example 5, and then the nitrogroup was reduced in ethanol using zinc powder and calcium chloride toobtain 4-[(1E)-3-(4-methylpiperazin-1-yl)-3-propen-1-ylaniline. ESI:246.

Reference Example 44

1-Boc-piperazine and 4-nitrobenzoyl chloride were allowed to undergo thereaction in DMF in the presence of triethylamine, and then the nitrogroup was reduced in the sama manner as the catalytic hydrogenationshown in Reference Example 3 to obtain tert-butyl4-(4-aminobenzoyl)piperazine-1-carboxylate. ESI: 307.

Reference Example 45

1-Boc-piperazine and 4-nitrobenzenesulfonyl chloride were allowed toundergo the reaction in DMF in the presence of triethylamine, and thenthe nitro group was reduced in the sama manner as the catalytichydrogenation shown in Reference Example 3 to obtain tert-butyl4-[(4-aminophenyl)sulfonyl]piperazine-1-carboxylate. FN: 340.

Reference Example 46

4-Iodonitrobenzene and tert-butyl 5-oxo-[1,4]diazepan-1-carboxylate wereallowed to undergo the reaction in 1,2-dichlorobenzene in the presenceof copper powder and potassium carbonate, and then the nitro group wasreduced in ethanol using zinc powder and calcium chloride to obtainbenzyl 4-(4-aminophenyl)-5-oxo-1,4-diazepan-1-carboxylate. ESI: 340.

Reference Example 47

After allowing tert-butyl4-[(4-nitrophenyl)acetyl]piperazine-1-carboxylate and methylbromoacetate to undergo the reaction in DMF in the presence of sodiumhydride, the nitro group was reduced in the same manner as the catalytichydrogenation shown in Reference Example 3, and then this was treatedwith lithium aluminum hydride and subjected to salt formation in thesame manner as in Reference Example 1 to obtain3-(4-aminophenyl)-4-(4-methylpiperazin-1-yl)butan-1-ol trihydrochloride.ESI: 264.

Reference Example 48

1-[(4-Nitrophenyl)acetyl]piperidine was alkylated with methylbromoacetate in the same manner as in Reference Example 47, hydrolyzedwith 1 M sodium hydroxide aqueous solution in methanol, and thencondensed with 1-methylpiperazine in the same manner as in ReferenceExample 5 to obtain1-methyl-4-[3-(4-nitrophenyl)-4-oxo-4-piperidin-1-ylbutanoyl]piperazine(ESI: 389). This piperazine compound was subjected to the reduction ofnitro group in the same manner as the catalytic hydrogenation shown inReference Example 3 and then treated with lithium aluminum hydride toobtain4-[3-(4-methylpiperazin-1-yl)-1-(piperidin-1-ylmethyl)propyl]aniline.ESI: 331.

In addition, the compounds of Reference Examples 49 to 51 were obtainedin the same manner as in Reference Example 2, and the compounds ofReference Examples 52 and 53 in the same manner as in Reference Example3, the compounds of Reference Examples 54 and 55 in the same manner asthe catalytic hydrogenation shown in Reference Example 3, the compoundsof Reference Examples 56 to 77 in the same manner as in ReferenceExample 7, the compound of Reference Example 78 in the same manner as inReference Example 9 the compounds of Reference Examples 79 to 86 in thesame manner as in Reference Example 11, the compound of ReferenceExample 87 in the same manner as in Reference Example 12, the compoundof Reference Example 88 in the same manner as in Reference Example 13,the compound of Reference Example 89 in the same manner as in ReferenceExample 14, the compounds of Reference Examples 90 to 103 in the samemanner as in Reference Example 16, the compounds of Reference Examples104 and 105 in the same manner as in Reference Example 19, the compoundsof Reference Examples 106 and 107 in the same manner as in ReferenceExample 23, the compound of Reference Example 108 in the same manner asin Reference Example 25, the compound of Reference Example 109 in thesame manner as in Reference Example 27, the compound of ReferenceExample 110 in the same manner as in Reference Example 32, the compoundof Reference Example 111 in the same manner as in Reference Example 33,the compound of Reference Example 112 in the same manner as in ReferenceExample 35, the compounds of Reference Examples 113 and 114 in the samemanner as in Reference Example 39, the compounds of Reference Examples115 to 118 in the same manner as in Reference Example 40, and thecompound of Reference Example 119 in the same manner as in ReferenceExample 42. Structures and physicochemical data of the compounds ofReference Examples 49 to 119 are shown in Tables 1 to 5.

Example 1

To 8 ml NMP solution of 750 mg of4-benzylamino-2-methylsulfonylpyrimidine-5-carboxamide were added 765 mgof 2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 1.07 ml ofdiisopropylethylamine, followed by stirring at 110° C. The reactionmixture was cooled down to room temperature, and then mixed with waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, and then the solvent was evaporated. The resultingresidue was purified by a silica gel column chromatography(chloroform:methanol:aqueous ammonia) and the resulting crude crystalswere recrystallized (methanol-ethyl acetate) to obtain 280 mg of4-benzylamino-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamideas colorless crystals.

Example 2

A 30 ml dichloromethane solution of 4.0 g of2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carbonyl chloride wasadded at −50° C. to a mixture of 1.32 g of 40% methylamine aqueoussolution, 2.53 ml of diisopropylethylamine and 10 ml of THF, followed bystirring for 30 minutes. This reaction mixture was poured into a mixtureof 30 ml 1 M hydrochloric acid and ice and extracted with chloroform.After washing the organic layer with saturated brine and subsequentlyevaporating the solvent, an 800 mg portion of 3.30 g the resulting5-carboxamide compound was made into 8 ml of NMP solution, mixed with1.05 g of 4-(2-aminoethyl)-2,6-dichlorophenol and 1.26 ml ofdiisopropylethylamine, followed by stirring overnight at 80° C. Thereaction mixture was cooled down to room temperature, and then mixedwith water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, and then the solvent was evaporated. Theresulting residue was purified by a silica gel column chromatography(chloroform:methanol) and then recrystallized (methanol-THF) to obtain265 mg of2-{[2-(3,5-dichloro-4-hydroxyphenyl)ethyl]amino}-N-methyl-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamideas colorless crystals.

Example 3

A 5 ml NMP solution of 352 mg of 4-morpholinoaniline was mixed with 0.95ml of 4 M hydrogen chloride/1,4-dioxane solution and 400 mg of4-benzylamino-2-chloropyrimidine-5-carboxamide, followed by stirring at90° C. for 3 hours. The reaction mixture was cooled down to roomtemperature, and then the precipitate was collected by filtration. Thecollected solid was mixed with saturated sodium bicarbonate aqueoussolution and extracted with a mixed solution of THF-ethyl acetate. Theorganic layer was washed with saturated brine, and then the solvent wasevaporated. The resulting residue was crystallized by adding methanoland then recrystallized (methanol-THF) to obtain 264 mg of4-benzylamino-2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidine-5-carboxamideas colorless crystals.

Example 4

At −7° C., 429 mg of mCPBA was gradually added to a 5 ml DMA solution of397 mg of4-benzylamino-2-{[4-(piperidin-1-ylmethyl)phenyl]amino}pyrimidine-5-carboxamide,followed by stirring for 30 minutes. After concentration of the reactionmixture, the resulting residue was purified by a silica gel columnchromatography (chloroform:methanol:aqueous ammonia) and thenrecrystallized (methanol-ethyl acetate) to obtain 228 mg of4-benzylamino-2-({4-[(1-oxidopiperidyl-1-yl)methyl]phenyl}amino)pyrimidine-5-carboxamideas colorless crystals.

Example 5

A 10 ml 1,4-dioxane solution of 738 mg of tert-butyl4-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-1-carboxylatewas mixed with 2.77 ml of 4 M hydrogen chloride/1,4-dioxane solution and3 ml of water, followed by stirring at 90° C. for 2 hours. The reactionmixture was cooled down to room temperature, diluted with water, mixedwith saturated sodium bicarbonate aqueous solution and then extractedwith an ethyl acetate-THF mixed solution. After washing of the organiclayer with saturated brine and subsequent evaporation of the solvent,the resulting solid was recrystallized (THF-ethanol) to obtain 413 mg of4-benzylamino-2-{[4-(piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxamideas ivory-colored crystals.

Example 6

A 7 ml DMF solution of 564 mg of4-benzylamino-2-{[4-(piperidin-4-yloxo)phenyl]amino}pyrimidine-5-carboxamidewas mixed with 175 mg of 35% aqueous formalin and 452 mg of sodiumtriacetoxy borohydride, followed by stirring at room temperature for 2hours. The reaction mixture was mixed with water and concentrated, andthe resulting residue was purified by a silica gel column chromatography(chloroform:methanol:aqueous ammonia) and then recrystallized(THF-methanol) to obtain 273 mg of4-benzylamino-2-{[4-(1-methylpiperidin-4-yloxo)phenyl]amino}pyrimidine-5-carboxamideas colorless crystals.

Example 7

A 20 ml portion of THF-methanol (2:1) mixed solution of 290 mg of4-[(2-benzyloxy-6-fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamidesynthesized in the same manner as in Production Example 13 was mixedwith 50 mg of 10% palladium-carbon, followed by stirring for 1 hour in ahydrogen atmosphere. The reaction mixture was filtered and then mixedwith 100 mg of 10% palladium-carbon, followed by stirring for 6 hours ina hydrogen atmosphere. After filtration of the reaction mixture andsubsequent evaporation of the solvent, the resulting residue waspurified by a silica gel column chromatography (chloroform-methanol). Byrecrystallizing the resulting crude crystals (THF-methanol), 117 mg of4-[(2-hydroxy-6-fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamidewas obtained as colorless crystals.

Example 8

A 5 ml pyridine solution of 304 mg of4-(2-aminobenzyl)amino-2-{[4-morpholin-4-yl]phenyl}amino)pyrimidine-5-carboxamidewas mixed with 0.1 ml of acetic anhydride under ice-cooling and thenfollowed by stirring at room temperature for 30 minutes. The reactionmixture was diluted with water, and then the precipitate was collectedby filtration. By washing the collected solid (methanol-THF), 285 mg of4-(2-acetylaminobenzyl)amino-2-{[4-morpholin-4-yl]phenyl}amino)pyrimidine-5-carboxamidewas obtained as a colorless solid.

Example 9

A 15 ml THF-methanol (1:1) solution of 750 mg of ethyl1-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxylatewas mixed with 1 M sodium hydroxide aqueous solution, followed bystirring under heating at 60° C. for 1 hour. The reaction mixture wascooled down to room temperature and mixed with 1 M sodium hydroxideaqueous solution, and the precipitated solid was collected by filtrationand washed with water and methanol. By recrystallizing the resultingsolid from a THF-methanol mixed solvent, 361 mg of1-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxylicacid was obtained as a colorless solid.

Example 10

Under ice-cooling, 0.05 ml of methanesulfonyl chloride was added to amixture of 300 mg of4-benzylamino-2-{[4-(2-aminomethylmorpholine-4-yl)phenyl]amino}pyrimidine-5-carboxamide,0.25 ml of triethylamine and 5 ml of DMF, followed by stirring at roomtemperature. After concentration of the reaction mixture, the resultingresidue was purified by a silica gel column chromatography(chloroform-methanol). The resulting crude crystals were dissolved in amethanol-THF mixed solution and mixed with 0.5 ml of 4 M hydrogenchloride/ethyl acetate solution, and the thus precipitated crystals werecollected by filtration and further recrystallized (ethanol-water) toobtain 285 mg of4-benzylamino-2-{[4-(2-{[methylsulfonyl)amino]methyl}morpholin-4-yl)phenyl]amino}pyrimidine-5-carboxamidehydrochloride as a colorless solid.

Example 11

A 5 ml portion of 1-methyl-2-pyrrolidone solution of 400 mg of4-benzylamino-2-[(4-piperazin-1-ylphenyl)amino]pyrimidine-5-carboxamidewas mixed with 0.12 ml of ethyl bromoacetate and 200 mg of potassiumcarbonate, followed by stirring at room temperature for 30 minutes. Thereaction mixture was mixed with water, and the organic layer wasextracted with ethyl acetate-THF mixed solvent. The organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, and then the residue obtained by evaporating the solvent waswashed with methanol to obtainethyl[4-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetateas a pale brown solid.

Example 12

A 5 ml THF-5 ml methanol solution of 680 mg of4-benzylamino-2-{[4-(2-N-methyl-N-Trifluoroacetylaminomethylmorpholin-4-yl)phenyl]amino}pyrimidine-5-carboxamidewas mixed with 518 mg of potassium carbonate and 4 ml of water, followedby stirring at room temperature. The reaction mixture was mixed withethyl acetate, washed with water and then concentrated. The resultingresidue was purified by a silica gel column chromatography(chloroform-methanol-aqueous ammonia) to obtain 500 mg of crudecrystals. A 120 mg portion of the crude crystals were dissolved in amethanol-THF mixed solution and mixed with 0.3 ml of 4 M hydrogenchloride/ethyl acetate solution, and the thus precipitated crystals werecollected by filtration and then recrystallized (ethanol-water) toobtain 110 mg of4-benzylamino-2-[(4-{2-[(methylamino)methyl]morpholin-4-yl}phenyl)amino]pyrimidine-5-carboxamidedihydrochloride as a pale green solid.

Example 13

A 780 mg portion of tert-butyl(2-{1-[4-(4-benzylamino-5-carbonylpyrimidin-2-ylamino)phenyl]piperidin-4-yl}ethyl)carbamatewas mixed with 10 ml of trifluoroacetic acid, followed by stirring atroom temperature for 1 hour. The solvent was evaporated, the resultingresidue was mixed with 1 M sodium hydroxide, and the thus formed solidwas collected by filtration. The solid was dissolved inchloroform-methanol, washed with saturated brine and then dried withanhydrous magnesium sulfate. The solvent was evaporated, and theresulting residue was dissolved in chloroform-methanol and mixed with 4M hydrogen chloride/dioxane solution. The solvent was evaporated, andthe resulting residue was recrystallized from THF-methanol-water toobtain 215 mg of2-({4-[4-(2-aminoethyl)piperidin-1-yl]phenyl}amino)-4-(benzylamino)pyrimidine-5-carboxamidetrihydrochloride as a colorless solid.

Example 14

A 5 ml methanol solution containing 80 mg of4-(benzylamino)-2-{[4-(β-D-acetylglucopyranosyloxy)phenyl]amino}pyrimidine-5-carboxamidewas mixed with sodium methoxide, followed by stirring overnight at roomtemperature. The reaction mixture was filtered by adding an ion exchangeresin (Dowex 50WX8-100) and then concentrated, and the resultingcrystals were washed with methanol to obtain 22 mg of4-(benzylamino)-2-{[4-(β-D-glucopyranosyloxy)phenyl]amino}pyrimidine-5-carboxamideas pale brown crystals.

Example 15

A 10 ml portion of 1-methyl-2-pyrrolidone solution containing 800 mg of2-{[4-(piperidin-4-yloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamidewas mixed with 0.12 ml of methyl iodide and 300 mg of potassiumcarbonate, followed by stirring at room temperature for 1 hour and thenat 60° C. for 30 minutes. A 0.1 ml portion of methyl iodide was furtheradded thereto, followed by stirring for 30 minutes. The reaction mixturewas cooled down to room temperature, mixed with water and then extractedwith an ethyl acetate-THF mixed solvent. The organic layer was washedwith water and saturated brine and then dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the resulting residue waspurified by a silica gel column chromatography(chloroform-methanol-aqueous ammonia) and further recrystallized fromethanol to obtain 197 mg of2-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamideas colorless crystals.

Production Example 1

A 6 ml portion of NMP solution containing 600 mg of2-(benzotriazol-1-yloxy)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidewas mixed with 538 mg of 2-(3-bromo-4-hydroxyphenyl)ethylamine and 0.72ml of diisopropylethylamine, followed by stirring at 80° C. for 2 hours.The reaction mixture was cooled down to room temperature, and then mixedwith water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, the solvent was evaporated, and then theresulting residue was recrystallized (ethanol-THF) to obtain 200 mg of2-{[2-(3-bromo-4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamideas colorless crystals.

Production Example 2

A 6 ml portion of NMP solution containing 533 mg of2-chloro-4-[(3-ethylphenyl)amino]pyrimidine-5-carboxamide was mixed with624 mg of 2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 0.87ml of diisopropylethylamine, followed by stirring at 80° C. for 4 hours.The reaction mixture was cooled down to room temperature, and then mixedwith water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, the solvent was evaporated, and then theresulting residue was recrystallized (methanol-THF) to obtain 460 mg of2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}-4-[(3-ethylphenyl)amino]pyrimidine-5-carboxamideas colorless crystals.

Production Example 3

A 8 ml portion of NMP solution containing 800 mg of2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-(methylsulfinyl)pyrimidine-5-carboxamidewas mixed with 373 mg of cyclohexylamine and 0.87 ml ofdiisopropylethylamine, followed by stirring at 100° C. for 1 hour. Thereaction mixture was cooled down to room temperature, and then mixedwith water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, and then the solvent was evaporated. Theresulting residue was purified by a silica gel column chromatography(chloroform:methanol), and the resulting crude crystals wererecrystallized (methanol-ethyl acetate) to obtain 547 mg of2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-cyclohexylaminopyrimidine-5-carboxamideas colorless crystals.

Production Example 4

A 4 ml portion of DMF solution containing 352 mg of2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylicacid was mixed with 223 mg of WSC hydrochloride, 157 mg of HOBt and 103mg of 2-dimethylaminoethylamine, followed by stirring overnight at roomtemperature. The reaction mixture was diluted with water and thenextracted with ethyl acetate. The organic layer was washed withsaturated brine and then the solvent was evaporated. The resultingresidue was purified by a silica gel column chromatography(chloroform:methanol:aqueous ammonia) and then recrystallized(hexane-ethyl acetate) to obtain 291 ng ofN-(2-dimethylaminoethyl)-2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamideas colorless crystals.

Production Example 5

A 10 ml portion of NMP solution containing 500 mg of2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidedihydrochloride synthesized by the method described in Example 8 of WO99/31073 was mixed with 0.53 ml of triethylamine and 0.12 ml of aceticanhydride, followed by stirring overnight at room temperature. Thereaction mixture was mixed with water and extracted with ethyl acetate,the organic layer was washed with saturated brine and then the solventwas evaporated. The resulting residue was triturated with methanol, andwashed to obtain 270 mg of2-({4-[(acetylamino)methyl]phenyl}amino)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamideas a pale yellow solid.

Production Example 6

A 20 ml acetic acid-10 ml THF mixed solution containing 500 mg of2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidedihydrochloride was mixed with 5.76 g of potassium-cyanate, which wasadded by dividing into 6 portions, at room temperature, followed bystirring for 6 hours. The reaction mixture was concentrated and thenpoured into water, and the precipitated solid was collected byfiltration and washed with acetonitrile. The resulting solid waspurified by a silica gel column chromatography (chloroform:methanol) toobtain 150 mg of4-[(3-methylphenyl)amino]-2-[(4-ureidomethylphenyl)amino]pyrimidine-5-carboxamideas a pale yellow solid.

Production Example 7

A 10 ml portion of NMP solution containing 1.0 g of2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidedihydrochloride was mixed with 0.83 ml of triethylamine and, underice-cooling, with 0.4 ml of trifluoroacetic anhydride, followed bystirring at room temperature for 2 hours. The reaction mixture wasdiluted with water and extracted with ethyl acetate. After washing theorganic layer with saturated brine, the solvent was evaporated, and theresidue was crystallized from chloroform-hexane to obtain 660 mg of atrifluoroacetylamino compound. A 7 ml portion of DMF solution containing640 mg of the trifluoroacetylamino compound was mixed with 400 mg ofpotassium carbonate and 0:11 ml of iodomethane, followed by stirringovernight at room temperature. The reaction mixture was diluted withwater and extracted with ethyl acetate, the organic layer was washedwith saturated brine, and then the solvent was evaporated. The resultingresidue was purified by a silica gel column chromatography(chloroform:methanol) to obtain 280 mg of an N-methyl compound. A 5 mlmethanol-5 ml THF mixed solution containing 160 mg of the N-methylcompound was mixed with 2 ml of concentrated aqueous ammonia, followedby stirring overnight at room temperature. The reaction mixture wasdiluted with water and extracted with ethyl acetate, the organic layerwas washed with saturated brine, and then the solvent was evaporated.The resulting solid was recrystallized (methanol-water) to obtain 100 mgof2-({4-[(methylamino)methyl]phenyl}amino)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamideas colorless crystals.

Production Example 8

A mixture of 1.0 g of2-chloro-4-(3-methylanilino)pyrimidine-5-carboxamide, 1.6 g oftert-butyl 4-aminobenzyl(2-morpholin-4-ylethyl)carbamate, 1.33 ml ofdiisopropylethylamine and 10 ml of NMP was stirred overnight at 130° C.The reaction mixture was cooled down to room temperature, and then mixedwith water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, the solvent was evaporated, and theresulting residue was purified by a silica gel column chromatography(chloroform:methanol). Then, a 750 mg portion of 780 mg of the resultingcompound was stirred overnight at room temperature in a mixed solutionof 75 ml methanol and 30 ml 6 M hydrochloric acid. The reaction mixturewas concentrated, and then the resulting crystals were washed withmethanol to obtain 510 mg of4-[(3-methylphenyl)amino]-2-[(4-{[(2-morpholin-4-ylethyl)amino]methyl}phenyl)amino]pyrimidine-5-carboxamidetrihydrochloride as colorless crystals.

Production Example 9

A 7 ml portion of DMF solution containing 685 mg of2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidedihydrochloride was mixed with 0.45 ml of triethylamine, 420 mg of 35%aqueous formalin and 1.09 g of sodium triacetoxy borohydride, followedby stirring overnight at room temperature. The reaction mixture wasmixed with water, concentrated and then purified by a silica gel columnchromatography (chloroform:methanol:aqueous ammonia) to obtain crudecrystals. This was dissolved in a methanol-ethyl acetate mixed solutionand mixed with 1 ml of 4 M hydrogen chloride/ethyl acetate solution, andthe thus precipitated crystals were collected by filtration and furtherrecrystallized (methanol-water) to obtain 164 mg of2-({4-[(dimethylamino)methyl]phenyl}amino)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamidedihydrochloride as colorless crystals.

Production Example 10

A mixture of 2.0 g of2-chloro-4-{(3-methylphenyl)amino}pyrimidine-5-carboxamide, 1.25 g of4-aminophenethyl alcohol, 1.99 ml of diisopropylethylamine and 10 ml ofNMP was stirred overnight at 110° C. The reaction mixture was cooleddown to room temperature and mixed with water and ethyl acetate, and thethus precipitated solid was collected by filtration and recrystallized(methanol) to obtain 560 mg of2-{[4-(2-hydroxyethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamideas pale yellow crystals.

Production Example 11

A 5 ml portion of NMP solution containing 300 mg of4-benzylamino-2-(methylsulfonyl)pyrimidine-5-carboxamide was mixed with122 mg of p-anisidine and 58 mg of potassium fluoride, followed bystirring at 90 to 100° C. for 21 hours. During this period, 58 mg ofpotassium fluoride was added three times. The reaction mixture wascooled down to room temperature, diluted with water, mixed withsaturated sodium bicarbonate aqueous solution and them extracted withethyl acetate. The organic layer was washed with saturated brine, andthen the solvent was evaporated. The resulting residue was purified by asilica gel column chromatography (chloroform:methanol) and thenrecrystallized (methanol-THF) to obtain 82 mg of4-benzylamino-2-[(4-methoxyphenyl)amino]pyrimidine-5-carboxamide ascolorless crystals.

Production Example 12

A 6 ml portion of NMP solution containing 303 mg of4-cyclohexylamino-2-(methylsulfonyl)pyrimidine-5-carboxamide was mixedwith 1.05 ml of 1 M n-tetrabutylammonium fluoride/THF solution, followedby stirring at 90° C. for 1 hour. Next, this was mixed with 200 mg of4-morpholinoaniline and 2.77 ml of 4 M hydrogen chloride/1,4-dioxanesolution, followed by stirring at 90° C. for 3 hours. The reactionmixture was cooled down to room temperature, diluted with water, mixedwith saturated sodium bicarbonate aqueous solution and then extractedwith ethyl acetate-THF mixed solution. The organic layer was washed withsaturated brine, and then the solvent was evaporated and the resultingresidue was purified by a silica gel column chromatography(chloroform:methanol) to obtain 54 mg of4-cyclohexylamino-2-[(4-morpholinophenyl)amino]pyrimidine-5-carboxamideas a pale brown solid.

Production Example 13

A mixture of 450 mg of4-methylsulfinyl-2-({4-[(N-oxidomorpholin-4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamide,0.29 ml of isopropylamine, 0.24 ml of diisopropylethylamine and 5 ml ofDMA was stirred at 80° C. for 3 hours. The reaction mixture was cooleddown to room temperature, mixed with 8 ml of 5% sodium hydrogen sulfite,followed by stirring for 1 hour. The reaction mixture was adjusted to pH9 by adding 0.5 ml of concentrated aqueous ammonia, diluted with waterand then extracted with chloroform. The organic layer was washed withsaturated brine, and then the solvent was evaporated. The resultingresidue was purified by a silica gel column chromatography(chloroform:methanol:aqueous ammonia), and the resulting pale brown oilwas crystallized from ethyl acetate to obtain 50 mg of2-{[4-(morpholinomethyl)phenyl]amino}-4-(2-propylamino)pyrimidine-5-carboxamideas colorless crystals.

Production Example 14

A 1 ml portion of chloroform solution containing 11.7 mg of4-methylsulfinyl-2-({4-[(N-oxidomorpholin-4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamidewas mixed with 5.1 mg of cyclopropylamine and 5.8 mg ofdiisopropylethylamine, followed by stirring at 90° C. for 15 hours. A 1ml portion of aqueous solution containing 50 mg of sodium hydrogensulfite was added to the reaction mixture, followed by stirring at roomtemperature for 4 hours. This was mixed with 0.1 ml of aqueous ammoniaand extracted with 2 ml of chloroform. By evaporating the solvent undera reduced pressure and fractionating the residue by an HPLC (Wakosil-II5C18AR, 0.1% HCOOH—H₂O/MeOH=7/3−0/10), 2.6 mg of4-cyclopropylamino-2-(4-morpholin-4-ylmethylphenylamino)-pyrimidine-5-carboxamidewas obtained.

Production Example 15

A 1 ml portion of THF solution containing 7.9 mg of4-benzylamino-2-chloropyrimidine-5-carboxamide and 3.7 mg of aniline,followed by stirring at 90° C. for 20 hours, which was then mixed with60 mg of PS-tosyl chloride (mfd. by Argonaut Technologies, 2.44 mmol/g),followed by stirring at room temperature for 3 hours. The reactionmixture was mixed with 2 ml of saturated sodium bicarbonate aqueoussolution and extracted with 2 ml of chloroform. By evaporating thesolvent under a reduced pressure, 6.6 mg of4-benzylamino-2-phenylaminopyrimidine-5-carboxamide was obtained.

Production Examples 16 to 57

A 960-mg portion of2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-(methylsulfinyl)pyrimidine-5-carboxamidewas dissolved in 100 ml of n-butanol and dispensed in 1.0 ml portionsinto 96 test tubes. DMF 1.0 M solutions of corresponding amine compoundswere added in 50 μl portions, followed by stirring at 100° C. for 10hours. The solvent was evaporated under a reduced pressure, and each ofthe resulting crude products was dissolved in 500 μl of methanol andpurified by HPLC fractionation using the molecular weight as the triggerby simultaneous measurement of MS, thereby obtaining the compounds ofProduction Examples 16 to 57.

Production Examples 58 to 73

Each of 2-chloro-4-(substituted amino)pyrimidine-5-carboxylic acidshaving various substituting amino groups on the 4-position of pyrimidinewas mixed with Rink Amide AM resin, which is prepared as an amine formby removal of Fmoc protecting group by piperazine treatment, and with amixed solvent of dichloromethane and DMF, further mixed with diisopropylcarbodiimide, followed by stirring at room temperature for 5 hours. Theresin was collected by filtration and washed with dichloromethane, DMF,THF and methanol in that order. The same series of washing was repeatedonce again, and finally washed with diethyl ether. By drying the resinunder a reduced pressure, various types of 2-chloro-4-(substitutedamino)pyrimidine-5-carboxamide (resin) adhered to the resin via thenitrogen atom of amido moiety were obtained. The resulting resins wererespectively added in 100 mg (equivalent to 40 μM) portions to two wellsof the reaction vessel of a synthesizer (SY-2000, Shimadzu Corp.). A 1.0ml portion of 0.5 M NMP solution of tyramine hydrochloride or2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 200 μl of 2.5 MNMP solution of diisopropylethylamine were added to each well and shakenat 100° C. for 12 hours. After discarding the reaction mixture byfiltration, each resin was washed with DMF (twice), dichloromethane,DMF, THF, methanol and THF in that order. The resin was mixed with 4 mlof dichloromethane solution of 40% trifluoroacetic acid and shaken atroom temperature for 5 minutes. Each resin was removed by filtration tocollect the reaction mixture. By evaporating the solvent under a reducedpressure, each of the compounds of Production Examples 58 to 73 wasobtained. Samples of compounds having a purity of 50% or less werepurified by HPLC fractionation using the molecular weight as the triggerby simultaneous measurement of MS.

Production Examples 74 to 93

A 1.09 g portion of2-[2-(4-hydroxyphenyl)ethylamino]-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylicacid was dissolved in 200 ml of DMF and dispensed in 2.0 ml portionsinto 96 test tubes. A 35 μl portion of 1.0 M HOBt/DMF solution and 70 mgof a PS-carbodiimide resin (mfd. by Argonaut Technologies) (1.0-1.5mmol/g) were added to each test tube. Subsequently, 1.0 M DMF solutionsof amine compounds corresponding to the target compounds were added in25 μl portions and shaken overnight at room temperature. By adding 70 mgof PS-tris amine resin (3-5 mmol/g) and stirring at room temperature for3 hours, unreacted2-{2-[(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylicacid and HOBt were bonded to the PS-tris amine resin. By removing theresin by filtration and evaporating the solvent under a reducedpressure, the compounds of Production Examples 74 to 93 were obtained.

The compounds of Examples 16 to 258 and Production Examples 94 to 275shown in the following Tables 6 to 20 were respectively obtained in thesame manner as the methods of the aforementioned Examples or ProductionExamples. Structures and physicochemical data of the compounds ofExamples 1 to 258 and Production Examples 1 to 275 are shown in thefollowing Tables 6 to 20.

In addition, structures of other compounds of the present invention areshown in Tables 21 to 25. These may be easily synthesized by using themethods described in the aforementioned production methods and examplesand the methods obvious to those skilled in the art, or modified methodsthereof.

TABLE 1

Rex R⁴ Dat  52

F: 267  53

F: 219  54

F: 191  55

F: 191  56

F: 290  57

NMR2: 2.55- 2.61(2H, m), 3.72-3.75(2H, m) 6.62-6.66(2H, m)  58

F: 220  59

F: 213 Sal: HCl  60

F: 193 Sal: 2HCl  61

F: 220  62

F: 306  63

F: 195 Sal: HCl  64

F: 256 Sal: HCl  65

ESI: 299  66

NMR2: 2.27(6H, s), 3.05-3.08 (4H, m) 3.63-6.67(2H, m)  67

NMR2: 1.48(9H, s), 3.12-3.19 (2H, m), 6.46-6.50 (2H, m)  68

F: 338  69

F: 269 Sal: HCl  70

F: 250  71

NMR2: 1.26 (3H, t, J = 7.2 Hz), 3.40- 3.48 (4H, m), 6.62- 6.66(2H, m). 72

F: 236  73

ESI: 290  74

ESI: 260  75

EI: 265  76

ESI: 390  77

ESI: 207 104

EI: 193 Sal: HCl 106

F: 207 107

F: 207 108

F: 193 109

F: 279 110

NMR1: 2.89(2H, s), 2.92-2.95(4H, m) 6.47-6.50 (2H, m) 111

NMR2: 1.46(9H, s), 4.05-4.08 (1H, m), 6.67-6.79(2H, m)

TABLE 2

Rex R³ R⁴ R⁵ n Dat 87 Cl HO Cl 2 F: 389 88 H

H 0 F: 392

TABLE 3 Rex Str Dat  49

F: 167  50

F: 181  51

F: 192 Sal HCl  78

F: 156 105

F: 209 Sal HCl 112

EI: 236 Sal HCl 113

F: 148 Sal HCl 114

F: 158 115

F: 194 Sal HCl 116

F: 162 Sal HCl 117

F: 194 Sal HCl 118

F: 156 Sal HCl 119

F: 167

TABLE 4

Rex R⁴ n Y—B Dat 79 HO 2 3-Me—Ph F: 365 80 HOCH₂CH₂ 0

F: 395 81 HOCH₂CH₂ 0

FN: 388 82 HOCH₂CH₂ 0 2,6-F₂—Ph F: 387 83 HOCH₂CH₂ 0 3,5-F₂—Ph F: 387 84HOCH₂CH₂ 0 2,5-F₂—Ph F: 387 85 HOCH₂CH₂ 0 3,4-F₂—Ph NMR: 2.69(2H, t, J =7.1 Hz), 7.32-7.44(2H, m), 8.70(1H, s) 86 HOCH₂CH₂ 0 2,4-F₂—Ph NMR:2.67(2H, t, J = 7.1 Hz), 7.07-7.09(4H, m), 8.69(1H, s)

TABLE 5

Rex Y—B X Dat  89 cHex MeSO₂ F: 299  90 3-CN—Ph Cl F: 274  91

Cl F: 293  92 Bn Cl F: 263  93 —CH₂—(2,6-F₂—Ph) Cl F: 299  94

Cl F: 293  95 —CH₂—(2-F₃C—Ph) Cl FN: 329  96 —CH₂—(2,3,6-F₃—Ph) Cl F:317  97 3-Et—Ph Cl F: 277  98 3-F₃C—Ph Cl F: 317  99

Cl FN: 305 100 —CH₂—(2-F—Ph) Cl F: 281 101 —CH₂—(2,5-F₂—Ph) Cl F: 299102

Cl F: 277 103 —CH₂—(2-O₂N—Ph) Cl F: 308

TABLE 6

Ex Syn R⁵ R¹ R² —Y—B Dat  1 Ex 1 H H H Bn F: 398; NMR1: 4.60-4.66 (2H,br m), 8.38(0.7H, s), 8.45(0.3H, s), 9.87(1H, s)  2 Ex 2 Cl Me H 3-Me—PhF: 446; NMR1: 2.75-2.79 (5H, m), 8.49(0.7H, s), 8.54(0.3H, s), 9.88(1H,s) 16 Ex 1 Cl H H Bn F: 432; NMR1: 4.60-4.66 (2H, br m), 8.38(0.7H, s),8.45(0.3H, s), 9.85(1H, s) 17 Pre 3 Cl H H CH₂—(2,5-F₂—Ph) F: 468

TABLE 7

Ex Syn —Y—B Dat 18 Ex 3 Bn F: 419 19 Pre 14 CH₂(3-Cl—Ph) F: 453 20 Pre14

F: 409 21 Pre 14

F: 425 22 Pre 14 CH₂—2Py F: 420 23 Pre 14 CH₂—3Py F: 420 24 Pre 14CH₂—4Py F: 420 25 Pre 14 CH₂(2-Cl—Ph) F: 453 26 Pre 14 CH₂(2-F₃C—Ph) F:487 27 Pre 14 CH₂(2-MeO—Ph) F: 449 28 Pre 14 CH₂(3-F₃C—Ph) F: 487 29 Pre14 CH₂(3-MeO—Ph) F: 449 30 Pre 14 CH₂(4-Cl—Ph) F: 453 31 Pre 14CH₂(4-F₃C—Ph) F: 487 32 Pre 14 CH₂(4-MeO—Ph) F: 449

TABLE 8

Ex Syn —Y—B Dat  3 Ex 3 Bn F: 405; NMR1: 3.71-3.74(4H, m), 4.66(2H, d, J= 6.3 Hz), 7.33-7.35 (4H, m), 8.51(1H, s)  7 Ex 7 CH₂—(2-F-6-HO—Ph) F:439; NMR1: 3.70-3.73(4H, m), 7.13-7.19 (1H, m), 8.47(1H, s), 10.25(1H,s)  8 Ex 8 CH₂—(2-AcHN—Ph) F: 462 33 Pre 13 CH₂—(2-Me—Ph) F: 419 34 Pre13 CH₂—(2-Cl—Ph) F: 439; NMR1: 2.95-3.03(m, 4H), 4.72(d, 2H, J = 5.9Hz), 7.48-7.53(m, 1H), 8.53(s, 1H) 35 Pre 13 CH₂—(2-MeO—Ph) F: 435;NMR1: 2.97-3.05(m, 4H), 3.85(s, 3H), 4.61(d, 2H, J = 5.8Hz), 8.50(s, 1H)36 Pre 13 CH₂—(2,4-F₂—Ph) F: 441 37 Pre 13 CH₂—(2,3,6-F₃—Ph) F: 459;NMR1: 3.00-3.08(m, 4H), 4.83(d, 2H, J = 5.9 Hz), 7.43-7.52 (1H, m),8.52(s, 1H) 38 Pre 13 CH₂—(3,5-F₂—Ph) F: 441; NMR1: 2.98-3.03(m, 4H),4.66(d, 2H, J = 5.8 Hz), 7.04-7.12(m, 1H), 8.52(s, 1H) 39 Pre 13CH₂—(2-F-5-Cl—Ph) FN: 455; NMR1: 2.98-3.04(4H; m), 4.67(d, 2H, J = 5.8Hz, 7.34-7.39(m, 1H), 8.53(1H, s) 40 Pre 13 CH₂—(2-HO—Ph) F: 421 41 Pre13 CH₂—(3-MeO—Ph) F: 435; NMR1: 2.97-3.05(4H, m), 3.70(s, 3H), 4.62(2H,d, J = 5.4 Hz), 8.51(1H, s) 42 Pre 13 CH₂—(2,5-(MeO)₂—Ph) F: 465; NMR1:2.96-3.04(4H, m), 3.80(s, 3H), 4.58(2H, d, J = 4.7 Hz), 8.50(1H, s) 43Pre 13 CH₂—(3-F—Ph) F: 423; NMR1: 2.97-3.04(4H, m), 4.67(2H, d, J = 5.9Hz), 7.34-7.41(m, 1H), 8.52(1H, s) 44 Pre 13 CH₂—(3-F₃C—Ph) F: 473;NMR1: 2.96-3.03(4H, m), 4.75(2H, d, J = 5.8 Hz), 6.95-7.04(m, 2H),8.52(1H, s) 45 Pre 13 CH₂—(2,3-(MeO)₂—Ph) F: 465; NMR1: 2.97-3.03(4H,m), 3.82(s, 3H), 4.64(2H, d, J = 5.9 Hz), 8.50(1H, s) 46 Pre 13

F: 407 47 Pre 13 CH₂—(3-HOCH₂—Ph) F: 433; NMR1: 2.95-3.04(4H, m),4.60(2H, d, J = 5.3 Hz), 4.68(2H, d, J = 5.9 Hz), 8.51 (1H, s) 48 Pre 13CH₂—(2,3-F₂—Ph) F: 441; NMR1: 2.97-3.03(4H, m), 4.74(2H, d, J = 5.9 Hz),7.28-7.36(m, 1H), 8.53(1H, s) 49 Pre 13 CH₂—(4-F—Ph) F: 423 50 Pre 13CH₂—(2-EtO—Ph) F: 449 51 Pre 13 CH₂—(2,4-(MeO)₂—Ph) F: 465 52 Pre 13CH₂—(2,6-Me₂—Ph) F: 433 53 Pre 13 CH₂—(2-F-5-Me—Ph) F: 437; NMR1:2.20(3H, s), 4.66(2H, d, J = 4.5 Hz), 7.08-7.11 (3H, m), 8.51(1H, s) 54Pre 13 CH₂—(2-(Et₂NCH₂)—Ph) F: 490 55 Pre 13 CH₂—(3-HO—Ph) F: 421; NMR1:2.96-3.05(4H, m), 4.58(2H, d, J = 5.9 Hz), 8.51(1H, s) 56 Pre 13CH₂—(3,5-(MeO)₂—Ph) F: 465 57 Pre 13 CH₂—(2-Me-3-Cl—Ph) FN: 451 58 Pre13 CH₂—(2-Cl-6-F—Ph) F: 457; NMR1: 3.00-3.06(4H, m), 4.84(2H, d, J = 4.4Hz), 8.52(1H, s) 59 Pre 13 CH₂—(2,6-F₂-3-Cl—Ph) FN: 473; NMR1:3.01-3.07(4H, m), 4.82(2H, d, J = 5.4 Hz), 7.18-7.26(m, 1H), 8.52(1H, s)60 Pre 13 CH₂—(2-F-6-MeO—Ph) F: 453; NMR1: 3.01-3.06(4H, m), 3.86(3H,s), 4.70(2H, d, J = 4.9 Hz); 8.48(1H, s) 61 Pre 13 CH₂—(2,6-Cl₂—Ph) F:473; NMR1: 3.01-3.06(4H, m), 4.92(2H, d, J = 4.9 Hz), 7.39-7.45(m, 1H),8.53(1H, s) 62 Ex 3 CH₂—(2-F—Ph) F: 423; NMR1: 3.01-3.03(4H, m),4.71(2H, d, J = 5.9 Hz), 7.12-7.16 (1H, m), 8.52(1H, s) 63 Ex 3CH₂—(2,6-F₂—Ph) F: 441; NMR1: 4.79(2H, d, J = 5.8 Hz), 7.40-7.47(1H, m),8.52(1H, s) 64 Ex 3 CH₂—(2,5-F₂—Ph) F: 441; NMR1: 2.97-3.05(4H, m),4.68(2H, d, J = 5.9 Hz), 7.28-7.33 (1H, m), 8.53(1H, s) 65 Ex 3CH₂—(2-F₃C—Ph) F: 473 66 Pre 13 CH₂—(2-HOCH₂—Ph) F: 434; NMR1:3.69-3.75(4H, m), 4.47(2H, d, J = 5.3 Hz), 4.65(2H, d, J = 5.8 Hz),8.51(1H, s) 67 Pre 13 CH₂—(2-OMe-6-Me—Ph) F: 449; NMR1: 3.70-3.75(4H,m), 3.81(3H, s), 4.65(2H, d, J = 5.3 Hz), 8.47(1H, s) 68 Pre 13CH₂—[2-HO(CH₂)₂O—Ph] F: 465; NMR1: 3.69-3.75(4H, m), 4.05(2H, t, J = 4.9Hz), 4.65(2H, d, J = 5.9 Hz), 8.49(1H, s) 69 Pre 13 CH₂—(2-OH-5-Cl—Ph)F: 455; NMR1: 3.71-3.76(4H, m), 4.56(2H, d, J = 5.9 Hz), 7.07-7.13(m,1H), 8.50(1H, s) 70 Pre 13 CH₂—(2-F-5-HOCH₂—Ph) F: 453; NMR1:3.71-3.74(4H, m), 4.40(2H, d, J = 5.9 Hz), 4.70(2H, d, J = 5.9 Hz),8.52(1H, s) 71 Pre 13 CH₂—[2-HO(CH₂)₂HN—Ph] F: 464 Sal: 3HCl 72 Pre 13CH₂[2-HO(CH₂)₂N(Me)—Ph] F: 478; NMR1: 2.70 (3H, s) 3.52-3.57(2H, m)3.70-3.73(4H, m), 4.74(2H, d, J = 5.8 Hz), 8.52 (1H, s) 73 Pre 13CH₂—(3-Et₂NCH₂—Ph) F: 490 74 Pre 13 CH₂—[2,6-(MeO)₂O—Ph] F: 465; NMR1:3.71-3.75(4H, m), 3.79(6H, s), 4.66(2H, d, J = 4.9 Hz), 8.46(1H, s) 75Pre 13 CH₂—[3-HO(CH₂)₂O—Ph] F: 465; NMR1: 3.70-3.75(4H, m), 3.91(2H, t,J = 4.9 Hz), 4.63(2H, d, J = 6.4 Hz), 8.51(1H, s) 76 Pre 13CH₂—(2-CF₃O—Ph) F: 489 77 Pre 13 CH₂—(2-F-6-CF₃—Ph) F: 491; NMR1:3.70-3.75(4H, m), 4.85(2H, d, J = 4.0 Hz), 7.62-7.71(m, 5H), 8.53(1H, s)78 Pre 13 CH₂—(3-F-6-CF₃—Ph) F: 491; NMR1: 3.69-3.74(4H, m), 4.86(2H, d,J = 5.9 Hz), 7.85-7.91(m, 1H), 8.56(1H, s) 79 Pre 13 CH₂—(2-F-3-CF₃—Ph)F: 491 80 Pre 13 CH₂—[2-HO(CH₂)₃—Ph] F: 463; NMR1: 1.68-1.75(2H, m),4.70(2H, d, J = 5.3 Hz), 8.53(1H, s) 81 Pre 13 CH₂—[3-HO(CH₂)₃—Ph] F:463; NMR1: 1.65-1.72(2H, m), 4.63(2H, d, J = 5.9 Hz), 8.51(1H, s) 82 Pre13 CH₂—[2-HO(CH₂)₂—Ph] F: 449; NMR1: 2.82(2H, t, J = 7.3 Hz), 6.80(2H,d, J = 8.8 Hz), 8.52(1H, s) 83 Pre 13 CH₂—[3-HO(CH₂)₂—Ph] F: 449; NMR1:2.70(2H, t, J = 7.0 Hz), 6.82(2H, d, J = 9.3 Hz), 8.51(1H, s) 84 Pre 13CH₂—(2-MeS—Ph) F: 451; NMR1: 3.73-3.78(4H, m), 4.67(2H, d, J = 5.3 Hz),7.26-7.39(m, 4H), 8.52(1H, s) Sal HCl 85 Pre 13 CH₂—(2,6-(HO)₂—Ph) F:437 86 Ex 3 CH₂—(2-MeSO₂—Ph) F: 483 87 Pre 13 CH₂[3-HO(CH₂)₂N(Me)—Ph] F:478; NMR1: 2.87(3H, s), 3.70-3.75(4H, m), 4.57(2H, d, J = 5.8 Hz),8.50(1H, s) Sal HCl 88 Pre 13 CH₂—(3-MeO-6-F—Ph) F: 453; NMR1:3.75-3.78(4H, m), 3.64(3H, s), 4.70(2H, d, J = 5.4 Hz), 8.55(1H, s) 89Pre 13 CH₂—(3-EtO₂C—Ph) F: 477 90 Pre 13 CH₂—[3-HO(CH₂)₂NH—Ph] FN: 462;NMR1: 3.70-3.75(4H, m), 4.54(2H, d, J = 5.9 Hz), 8.55(1H, s) 91 Pre 13CH₂—(2-MeO-5-F—Ph) F: 453; NMR1: 3.71-3.75(4H, m), 3.85(3H, s), 4.60(2H,d, J = 5.9 Hz), 8.52(1H, s) 92 Pre 13 CH₂—(2,3,5-F₃—Ph) F: 459; NMR1:3.71-3.76(4H, m), 4.73(2H, d, J = 5.9 Hz), 7.35-7.47(m, 3H), 8.54(1H, s)93 Ex 3 CH₂—(2-O₂N—Ph) F: 450; NMR1: 3.72-3.75(4H, m), 4.95(2H, d, J =5.9 Hz), 8.14(1H, d, J = 7.8 Hz), 8.51(1H, s) 94 Ex 7 CH₂—(2-H₂N—Ph) F:420 95 Pre 13 CH₂—(3-Cl—Ph) F: 439; NMR1: 3.70-3.75(4H, m), 4.65(2H, d,J = 5.8 Hz), 7.33-7.39(m, 2H), 8.52(1H, s) 96 Pre 13

F: 441; NMR1: 3.69-3.74(4H, m), 4.84(2H, d, J = 5.9 Hz), 7.36-7.40(m,1H), 8.52(1H, s) 97 Pre 13

F: 445; NMR1: 3.70-3.75(4H, m), 4.74(2H, d, J = 6.4 Hz), 8.52(1H, s) 98Pre 13

F: 445; NMR1: 3.70-3.75(4H, m), 4.79(2H, d, J = 5.8 Hz), 7.47-7.54(m,3H), 8.54(1H, s) 99 Pre 13

F: 412

TABLE 9

Ex Syn R⁴ —Y—B Dat  4 Ex 4 

Bn F: 433  5 Ex 5 

Bn F: 404  6 Ex 6 

Bn F: 433; NMR1: 4.20-4.26(1H, m), 4.66 (2H, d, J = 5.8 Hz), 8.53(1H, s) 9 Ex 9 

Bn F: 447  10 Ex 10

Bn F: 512; NMR1: 2.94 (3H, s), 4.67 (2H, d, J = 5.8 Hz), 8.55 (1H, s)Sal: HCl  11 Ex 11

Bn NMR1: 1.18(3H, t, J = 7.2 Hz), 4.66 (2H, d, J = 6.0 Hz), 8.51(1H, s) 12 Ex 12

Bn F: 448; NMR1: 2.70-2.75 (1H, m), 4.68 (2H, d, J = 5.8 Hz), 8.61 (1H,s) Sal: 2HCl  13 Ex 13

Bn F: 446; NMR1: 2.80-2.88(2H, m), 4.71 (2H, d, J = 5.9 Hz), 8.68(1H, s)Sal: 3HCl  14 Ex 14

Bn F: 498 100 Ex 3 

Bn F: 433 101 Ex 3 

Bn F: 435 102 Ex 3 

Bn F: 417 103 Ex 3 

Bn F: 432 Sal: 3HCl 104 Ex 3 

Bn F: 467 105 Ex 3 

Bn F: 403; NMR1: 3.00-3.03 (4H, m), 4.66 (2H, d, J = 5.9 Hz), 8.51 (1H,s) 106 Ex 3 

Bn F: 431 107 Ex 3 

Bn F: 447; NMR1: 2.08(3H, s), 4.69(2H, d, J = 5.8 Hz), 8.55(1H, s) 108Ex 3 

Bn F: 431; NMR1: 1.50(4H, br), 4.71 (2H, d, J = 5.9 Hz), 8.58(1H, s) 109Ex 3 

Bn F: 467 110 Ex 3 

Bn F: 460 111 Ex 3 

Bn F: 445 112 Ex 3 

Bn F: 459 113 Ex 3 

Bn F: 453; NMR1: 3.66-3.68(4H, m), 4.67 (2H, d, J = 5.9 Hz), 8.52(1H, s)114 Ex 3 

Bn F: 417; NMR1: 2.36(2H, t, J = 6.3 Hz), 4.69 (2H, d, J = 5.9 Hz),8.56(1H, s) 115 Ex 3 

Bn F: 417 116 Ex 3 

Bn F: 418; NMR1: 2.24(3H, s), 4.66(2H, d, J = 5.8 Hz),8.51(1H, s) 117 Ex3 

Bn F: 433; NMR1: 3.65-3.72 2H, m), 4.67 (2H, d, J = 6.3 Hz), 8.52(1H, s)118 Ex 3 

Bn F: 433; NMR1: 4.00-4.07(2H, m), 4.66 (2H, d, J = 5.8 Hz), 8.51(1H, s)119 Ex 3 

Bn F: 433; NMR1: 3.49(4H, br), 4.71 (2H, d, J = 5.8 Hz), 8.58(1H, s) 120Ex 3 

Bn F: 448 121 Ex 3 

Bn F: 462 122 Ex 3 

Bn F: 432 123 Ex 3 

Bn F: 419 124 Ex 3 

Bn F: 432 125 Ex 3 

Bn F: 446; NMR1: 0.996(6H, d, J = 6.4 Hz), 4.66(2H, d, J = 5.9 Hz),8.50(1H, s) 126 Ex 3 

Bn F: 462 127 Ex 3 

Bn F: 419; NMR1: 1.88(2H, quint, J = 5.8 Hz), 4.65(2H, d, J = 5.9 Hz),8.56(1H, s) 128 Ex 5 

Bn F: 419; NMR1: 4.34-4.40(1H, m), 4.66 (2H, d, J = 5.9 Hz), 8.53(1H, s)129 Ex 5 

Bn FN: 414 130 Ex 5 

Bn F: 432 131 Ex 6 

Bn F: 430 132 Ex 6 

Bn F: 446 133 Pre 15

Bn F: 417 134 Ex 3 

Bn F: 389 Sal HCl 135 Ex 3 

Bn F: 405; NMR1: 2.00-2.07(1H, m), 6.39(2H, d, J = 3.8 Hz), 8.48(1H, s)136 Ex 3 

Bn F: 446; NMR1: 1.81(3H, s), 4.30-4.40 (1H, m), 6.53(2H, d, J = 7.8 Hz)Sal: 2HCl 137 Ex 3 

Bn F: 418; NMR1: 3.84-3.87(1H, m), 4.67 (2H, d, J = 5.6 Hz), 6.57(2H, d,J = 8.3 Hz) Sal: 2HCl 138 Ex 3 

Bn F: 449; NMR1: 3.70-3.75(4H, m), 4.68 (2H, d, J = 5.9 Hz), 8.64(1H, s)Sal: 2HCl 139 Ex 3 

Bn F: 414; NMR1: 2.17-2.15(1H, m), 4.65 (2H, d, J = 5.9 Hz), 8.50(1H, s)140 Ex 3 

Bn F: 446; NMR1: 3.75-3.80(4H, m), 4.80 (2H, d, J = 5.3 Hz), 8.56(1H, s)Sal: 2HCl 141 Ex 3 

Bn F: 508; NMR1: 3.40-3.85(4H, m), 4.66 (2H, d, J = 6.3 Hz), 8.52(1H, s)142 Ex 3 

Bn F: 495 Sal: HCl 142 Ex 3 

Bn F: 475; NMR1: 2.15(6H, s), 4.66(2H, d, J = 5.9 Hz), 8.51(1H, s) 144Ex 3 

Bn F: 421; NMR1: 4.66(2H, d, J = 5.4 Hz), 4.70-4.90(1H, m), 8.51(1H, s)145 Ex 3 

Bn F: 439; NMR1: 3.29-3.39(2H, m), 4.67 (2H, d, J = 5.8 Hz), 8.51(1H, s)146 Ex 3 

Bn F: 482; NMR1: 3.29-3.39(2H, m), 4.67 (2H, d, J = 5.8 Hz), 8.51(1H, s)Sal: HCl 147 Ex 3 

Bn F: 534; NMR1: 3.64-3.72(2H, m), 4.71 (2H, d, J = 6.3 Hz), 8.61(1H, s)Sal: 3HCl 148 Ex 3 

Bn F: 489; NMR1: 2.83(6H, s), 4.68(2H, d, J = 5.8 Hz), 8.60(1H, s) Sal:2HCl 149 Ex 3 

Bn F: 447; NMR1: 1.18-1.30(2H, m), 4.66(2H, d, J = 5.9 Hz), 8.51(1H, s)150 Ex 3 

Bn NMR1: 1.19(3H, t, J = 7.2 Hz), 4.66(2H, d, J = 6.0 Hz), 8.51(1H, s)151 Ex 3 

Bn F: 516; NMR1: 3.81-3.97(4H, m), 4.70 (2H, d, J = 5.9 Hz), 8.63(1H, s)Sal: 3HCl 152 Pre 4

Bn F: 517; NMR1: 2.77(s, 3H), 3.13-3.17 (2H, m), 4.70(2H, d, J = 6.4 Hz)Sal: 3HCl 153 Ex 3 

Bn F: 534; NMR1: 1.39 (9H, s), 2.29 (1H, t, J = 11.2 Hz), 8.51 (1H, s)154 Ex 5 

Bn F: 434; NMR1: 2.70-2.75 (1H, m), 4.68 (2H, d, J = 5.8 Hz), 8.61 (1H,s) Sal: 2HCl 155 Ex 6 

Bn F: 462; NMR1: 2.68-2.74 (1H, m), 4.67 (2H, d, J = 5.9 Hz), 8.52 (1H,s) Sal: 2HCl 156 Ex 8 

Bn F: 476; NMR1: 1.84 (3H, s), 2.41 (1H, t, J = 11.3 Hz), 8.53 (1H, s)Sal: HCl 157 Pre 4

Bn F: 519; NMR1: 4.69 (2H, d, J = 5.9 Hz), 7.11 (2H, brd, J = 6.8 Hz),8.69 (1H, s) Sal: 2HCl 158 Ex 9 

Bn F: 462 Sal: HCl 159 Pre 4

Bn MP: 218-223; NMR1: 2.73(3H, s), 4.69(2H, d, J = 5.8 Hz), 8.62(1H, s)Sal: 3HCl 160 Ex 3 

Bn F: 419; NMR1: 4.51-4.58(1H, m), 4.78(2H, d, J = 5.8 Hz), 8.57(1H, s)161 Ex 3 

Bn F: 433; NMR1: 2.82(1.5H, s), 2.89 (1.5H, s), 4.70(2H, d, J = 5.9 Hz),8.58 (0.5H, s), 8.60(0.5H, s) Sal: HCl 162 Ex 3 

Bn F: 419; NMR1: 2.74(3H, s), 4.75(2H, d, J = 6.4 Hz), 8.61(1H, s) Sal:2HCl 163 Ex 3 

Bn F: 419; NMR1: 4.58-4.62(1H, m), 4.71 (2H, d, J = 5.8 Hz), 8.61(1H, s)Sal: HCl 164 Ex 3 

Bn F: 433; NMR1: 2.69(3H, s), 4.70(2H, d, J = 5.8 Hz), 8.61(1H, s) Sal:HCl 165 Ex 9 

Bn F: 461 166 Ex 3 

Bn NMR1: 1.78-1.22(3H, m), 4.66(2h, d, J = 6.0 Hz), 8.51(1H, s) 167 Ex9 

Bn F: 504 168 Ex 3 

Bn NMR1: 3.58(3H, s), 4.67(2H, d, J = 4.0 Hz), 8.51(1H, s) 169 Ex 5 

Bn F: 405; NMR1: 4.23-4.32(1H, m), 4.68-4.81 (2H, m), 8.65(1H, s) Sal:2HCl 170 Ex 3 

Bn F: 505 171 Ex 6 

Bn F: 419; NMR1: 4.35-4.45(1H, m), 4.71 (2H, d, J = 5.9 Hz), 8.67(1H, s)Sal: 2HCl 172 Ex 3 

Bn F: 419; NMR1: 4.58-4.62(1H, m), 4.71 (2H, d, J = 5.8 Hz), 8.61(1H, s)Sal: HCl 173 Ex 3 

Bn F: 433; NMR1: 2.69(3H, s), 4.70(2H, d, J = 5.8 Hz), 8.61(1H, s) Sal:HCl 174 Ex 5 

Bn F: 405; NMR1: 4.23-4.32(1H, m), 4.68-4.81(2H, m), 8.65(1H, s) Sal:2HCl 175 Ex 3 

Bn F: 505 176 Ex 6 

Bn F: 419; NMR1: 4.35-4.45(1H, m), 4.71(2H, d, J = 5.9 Hz), 8.67(1H, s)Sal: 2HCl 177 Ex 3 

Bn F: 525; NMR1: 2.70 (1H, br t, J = 10.3 Hz), 4.53(2H, s), 8.53 (1H,s). Sal: HCl 178 Ex 7 

Bn F: 435; NMR1: 2.54-2.60 (1H, m), 4.68 (2H, d, J = 5.9 Hz), 8.57 (1H,s) Sal: HCl 179 Ex 3 

Bn F: 544 (ESI) 180 Ex 10

Bn F: 526; NMR1: 2.86 (3H, s), 2.92 (3H, s), 8.55 (1H, s) Sal: HCl 181Ex 3 

Bn F: 546 182 Ex 13

Bn F: 461 NMR1: 2.06-2.33(2H, m), 4.68 (2H, d, J = 5.9 Hz), 8.60(1H, s)Sal: 3HCl 183 Ex 3 

Bn F: 561 184 Ex 3 

Bn F: 543; NMR1: 1.19(3H, t, J = 7.1 Hz), 4.82(2H, d, J = 5.4 Hz),8.51(1H, s) 185 Ex 9 

Bn F: 515; NMR1: 2.19(2H, d, J = 6.8 Hz), 4.82(2H, d, J = 5.9 Hz),8.51(1H, s) 186 Ex 3 

Bn F: 666 187 Ex 3 

F: 469

TABLE 10

Ex Syn R⁴ Dat  15 Ex 15

F: 487; NMR1: 2.17(3H, s), 4.82(2H, d, J = 5.8 Hz), 8.52(1H, s) 188 Ex3 

F: 487; NMR1: 2.90(3H, s), 4.88(2H, d, J = 5.9 Hz), 8.63(1H, s) Sal: HCl189 Ex 3 

F: 544; NMR1: 1.20(3H, t, J = 7.1 Hz), 4.83(2H, d, J = 5.4 Hz), 8.52(1H,s) 190 Ex 9 

F: 516; NMR1: 3.20(2H, s), 4.83(2H, d, J = 5.9 Hz), 8.52(1H, s) 191 Ex3 

F: 473; NMR1: 3.70-3.76(4H, m), 4.85(2H, d, J = 5.9 Hz), 8.52(1H, s)Sal: HCl 192 Ex 3 

F: 487; NMR1: 2.78(3H, d, J = 3.9 Hz), 4.81-4.89 (2H, m), 8.64(1H, s)Sal: 2HCl 193 Ex 3 

F: 499; NMR1: 3.72-3.81(1H, m), 4.85(2H, d, J = 5.6 Hz), 8.69(1H, s)Sal: 2HCl 194 Ex 5 

F: 459; NMR1: 4.40-4.48(1H, m), 4.88 (2H, d, J = 5.4 Hz), 8.69(1H, s)Sal: 2HCl 195 Ex 3 

F: 572 196 Ex 9 

F: 544 197 Ex 3 

F: 531 198 Ex 9 

F: 503 199 Ex 3 

F: 531 NMR1: 4.59-4.64(1H, m), 4.84(2H, d, J = 5.8 Hz), 8.52(1H, s) Sal:HCl 200 Ex 3 

F: 543 NMR1: 1.63-1.70(2H, m), 4.83(2H, d, J = 5.9 Hz), 8.51(1H, s) 201Ex 3 

F: 515 NMR1: 4.02(2H, s), 4.86(2H, d, J = 5.9 Hz), 8.67(1H, s) Sal: 2HCl202 Ex 13

F: 473; NMR1: 4.25-4.32(1H, m), 4.83(2H, d, J = 5.9 Hz), 8.53(1H, s) 203Ex 3 

F: 573 204 Ex 3 

F: 473; NMR1: 2.27(3H, s), 4.82(2H, d, J = 5.3 Hz), 8.52(1H, s) 205 Ex13

F: 473; NMR1: 4.11-4.16(1H, m), 4.82(2H, d, J = 5.9 Hz), 8.53(1H, s) 206Ex 3 

NMR2: 1.42(9H, s), 4.83(2H, d, J = 5.6 Hz), 8.24(1H, s) 207 Ex 11

F: 559; NMR1: 1.17(3H, t, = 7.1 Hz), 4.82(2H, d, J = 5.8 Hz), 8.52(1H,s) 208 Ex 9 

F: 531; NMR1: 1.17-1.98(4H, m), 4.83(2H, d, J = 5.9 Hz), 8.54(1H, S) 209Ex 3 

F: 503; NMR1: 4.42-4.44 (2H, m), 4.85 (2H, d, J = 5.9 Hz), 8.58 (1H, s)Sal: 2HCl 210 Ex 3 

F: 472; NMR1: 4.85 (2H, d, J = 5.9 Hz) 7.01 (2H, d, J = 9.2 Hz), 8.57(1H, s) Sal: 2HCl 211 Ex 3 

F: 558; NMR1: 1.51-1.58(2H, m), 4.82(2H, d, J = 5.9 Hz), 8.51 (1H, s)212 Ex 3 

F: 501; NMR1: 2.10 (3H, s), 3.49 (2H, s), 8.55 (1H, s) 213 Ex 3 

F: 486; NMR1: 4.85 (2H, d, J = 5.8 Hz), 6.78 (2H, d, J = 8.3 Hz), 8.57(1H, br s) Sal: 2HCl 214 Ex 3 

F: 573 Sal: HCl 215 Ex 3 

ESI: 622 216 Ex 5 

F: 522 217 Ex 3 

F: 499; NMR1: 1.34-1.40 (1H, m), 2.96-3.01 (2H, m), 4.88 (2H, d, J = 5.8Hz), 8.67 (1H, s) Sal: 2HCl 218 Ex 3 

F: 526 Sal: 2HCl 219 Ex 3 

F: 544 Sal: 2.9HCl 220 Ex 3 

F: 611 Sal: 3.7HCl 221 Ex 3 

ESI: 670 222 Ex 5 

F: 570; NMR1: 3.04-3.13(4H, m), 4.86(2H, d, J = 5.8 Hz), 7.44-7.56(4H,m), 8.65(1H, s) Sal: 3HCl 223 Ex 6 

F: 584; NMR1: 2.75(3H, d, J = 4.3 Hz), 2.95-3.07(2H, m), 4.86(2H, d, J =5.9 Hz), 8.61(1H, s) Sal: 2HCl 224 Ex 3 

F: 545 225 Ex 5 

F: 445; NMR1: 3.93-4.03(2H, m), 4.83(2H, d, J = 5.8 Hz), 5.03-5.11(1H,m), 8.59(1H, s) Sal: 2HCl 226 Ex 6 

F: 459; NMR1: 3.98-4.07(1H, m), 4.83(2H, d, J = 5.9 Hz), 4.93-5.01(0.5H,m), 5.13-5.20(0.5H, m), 8.62(1 H, s) Sal: 2HCl 227 Ex 3 

F: 540; NMR1: 1.70-2.29 (7H, m), 3.50 (2H, d, J = 11.1 Hz), 4.86 (2H, d,J = 5.8 Hz), 8.64 (1H, s) Sal: 3HCl 228 Ex 3 

F: 570 Sal: 2HCl 229 Ex 3 

ESI: 586 230 Ex 5 

F: 486 Sal: 2HCl 231 Ex 3 

ESI: 620 232 Ex 7 

F: 486; NMR1: 2.94-2.96 (2H, br d), 4.03 (2H, br), 7.48-7.52 (1H, m),8.60 (1H, s) Sal: 2HCl 233 Ex 14

F: 552; NMR1: 4.83(2H, d, J = 5.8 Hz), 5.25-5.30(1H, m), 8.53(1H, s) 234Ex 14

F: 536 235 Pre 15

ESI: 507 236 Pre 15

ESI: 473 237 Pre 15

ESI: 486 238 Pre 15

ESI: 473

TABLE 11

Ex Syn R³ R⁴ R⁵ —Y—B Dat 239 Ex 3 H

F Bn F: 423; NMR1: 4.69(2H, d, J = 6.4 Hz), 6.90(1H, t, J = 9.3 Hz),8.55(1H, s) 240 Ex 3 H

F₃C Bn F: 473 241 Ex 3

H H Bn F: 405 242 Ex 3

H H Bn F: 433; NMR1: 2.41-2.45 (2H, m), 4.72(2H, d, J = 5.9 Hz),8.62(1H, s) 243 Ex 3

H H Bn F: 419 244 Ex 3 H

F

F: 459; NMR1: 4.81(2H, d, J = 5.4 Hz), 6.95-7.00(1H, m), 8.55(1H, s) 245Ex 3 F

F Bn F: 441 246 Ex 3 F

H

F: 441; NMR1 2.91-2.93(4H, m), 4.75(2H, d, J = 5.8 Hz), 8.57(1H, s,) 247Ex 3 F

H

F: 459; NMR1: 4.72(2H, d, J = 6.1 Hz), 6.86-6.90(1H, m), 8.57(1H, s) 248Ex 3

H H Bn F: 449; NMR1 4.35-4.42(2H, m), 4.75(2H, d, J = 6.4 Hz), 8.69(1H,s) Sal: 2HCl 249 Ex 3

H H Bn F: 448; NMR1: 3.37-3.47 (4H, m), 4.73(2H, d, J = 5.8 Hz),8.56(1H, s) Sal: 2HCl 250 Ex 3

H H Bn F: 462; NMR1: 2.85(3H, s), 4.74(2H, d, J = 5.8 Hz), 8.64 (1H, s)Sal: 2HCl 251 Ex 3

H Bn F: 534; NMR1: 3.67-3.71 (4H, s), 4.72(2H, d, J = 5.9 Hz), 8.54(1H,s) 252 Ex 3 HOCH₂—

H Bn F: 435; NMR1: 4.53(2H, s), 4.71(2H, d, J = 5.9 Hz), 8.53 1H, s) 253Pre 15

H H

ESI: 543 254 Pre 15 Et₂NCH₂— H H

ESI: 459 255 Pre 15 HO₂C—

H

ESI: 531 256 Pre 15

H H

ESI: 459 257 Pre 15

H H

ESI: 473 258 Ex 3

H H

F: 487; NMR1: 3.09-3.14(4H, m), 3.81-3.87(2H, m), 4.89 (2H, d, J = 5.9Hz), 8.68(1H, s) Sal: 2HCl

TABLE 12

Pre Syn —Y—B Dat 16 — 4-Me-cHex F: 438 17 — cBu F: 396 18 — cPen F: 41019 —

F: 436 20 —

F: 478 21 —

F: 462 22 —

F: 452 23 — cHep F: 438 24 — cOct F: 452 25 — 2Ad F: 476 26 —CH₂-(2-Cl—Ph) F: 466 27 — CH₂-(2-Br—Ph) F: 510 28 — CH₂-(2,6-F₂—Ph) F:468 29 — CH₂-(3-F—Ph) F: 450 30 — CH₂-(3-Cl—Ph) F: 466 31 —CH₂-(2,6-F₂—Ph) F: 468 32 —

F: 422 33 —

F: 438 34 —

F: 426 35 — CH₂—tBu F: 412 36 — (CH₂)₂CHMe₂ F: 412 37 —

F: 457 38 —

F: 458 39 —

F: 462 40 —

F: 476 41 —

F: 472 42 — 3-HO—Ph F: 434 43 — 4-MeO—Ph F: 448 44 — CH₂-(2-F₃C—Ph) F:500 45 — CH₂-(2-MeO—Ph) F: 462 94 Ex 1 cHex F: 424 95 Pre 3 CH₂CHMe₂ F:398 96 Pre 3 CH(Me)Ph F: 446 97 Pre 3

F: 436 98 Pre 4

F: 462

TABLE 13

Pre Syn R³ R⁴ R⁵ —Y—B Dat  1 Pre 1 Br HO H 3-Me—Ph F: 443; NMR1:2.75(2H, t, J = 7.3 Hz), 8.55(0.8H, s), 8.61(0.2H, s), 9.99(1H, s)  2Pre 2 Cl HO H 3-Et—Ph F: 412  58 — Cl HO H 3Qui F: 435  59 — Cl HO H2-Me—Ph F: 398  60 — Cl HO H 3-iPr—Ph F: 426  61 — Cl HO H 3-HOCH₂—Ph F:414  62 — Cl HO H 3-MeS—Ph F: 430  63 — Cl HO H 4-Me—Ph F: 398  64 — ClHO H 3,5-Me₂—Ph F: 412  65 — Cl HO H 3,5-Cl₂—Ph F: 453  66 — Cl HO H3-Ac—Ph F: 426  67 — Cl HO H 4-F-3-Me—Ph F: 416  68 — Cl HO H 2,4-F₂—PhF: 420  69 — Cl HO H CH₂-(3-Me—Ph) F: 412  99 Pre 1 Cl HO H 3-Me—Ph F:398; NMR1: 2.75(2H, t, J = 6.9 Hz), 8.55(0.7H, s), 8.61(0.3H, s),9.91(1H, s) 100 Pre 1 H AcNH H 3-Me—Ph F: 405 101 Pre 1 HO H H 3-Me—PhF: 364 102 Pre 1 H MeSO₂NH H 3-Me—Ph F: 441 103 Pre 1 H HCOHN H 3-Me—PhF: 391 104 Pre 1 F HO H 3-Me—Ph F: 382; NMR1: 2.75(2H, t, J = 7.3 Hz),8.55(0.7H, s), 8.61(0.3H, s), 9.58(1H, s) 105 Pre 1 MeO HO H 3-Me—Ph F:394 106 Pre 1 Me HO H 3-Me—Ph F: 378 107 Pre 1 MeO HO MeO 3-Me—Ph F: 424108 Pre 1 Cl HO Cl 3-Me—Ph F: 432; NMR1: 2.77(2H, t, J = 7.3 Hz),8.55(0.7H, s), 8.61(0.3H, s), 9.88(1H, s) 109 Pre 1 Cl HO H

F: 428; NMR1: 5.12(1H, d, J = 3.9 Hz), 8.54(0.7H, s), 8.61(0.3H, s),9.90(1H, s) 110 Pre 2 Cl HO H 3-NC—Ph F: 409 111 Pre 2 Cl HO H

F: 428 112 Ex 1 Cl HO H cHex F: 390

TABLE 14

Pre Syn R³ R⁵ R¹ R² —Y—B Dat  4 Pre 4 H H (CH₂)₂NMe₂ H 3-Me—Ph F: 435 74 — H H

H 3-Me—Ph F: 504  75 — H H

H 3-Me—Ph F: 491  76 — H H (CH₂)₂OMe H 3-Me—Ph F: 422  77 — H H

H 3-Me—Ph F: 475  78 — H H (CH₂)₃NMe₂ H 3-Me—Ph F: 449  79 — H H(CH₂)₃OMe H 3-Me—Ph F: 436  80 — H H

H 3-Me—Ph F: 503  81 — H H

H 3-Me—Ph F: 472  82 — H H OMe H 3-Me—Ph F: 394  83 — H H (CH₂)₃NMe₂ H3-Me—Ph F: 463  84 — H H

H 3-Me—Ph F: 475  85 — H H (CH₂)₂—3Py H 3-Me—Ph F: 469  86 — H H CH₂—3PyH 3-Me—Ph F: 455  87 — H H

H 3-Me—Ph F: 489  88 — H H

H 3-Me—Ph F: 461  89 — H H

H 3-Me—Ph F: 448  90 — H H

H 3-Me—Ph F: 475  91 — H H

H 3-Me—Ph F: 470  92 — H H (CH₂)₂SMe H 3-Me—Ph F: 438  93 — H H CH₂—2PyH 3-Me—Ph F: 455 113 Ex 2 H H Me H 3-Me—Ph F: 378 114 Ex 2 H H Me Me3-Me—Ph F: 392 115 Ex 2 H H Et H 3-Me—Ph F: 392 116 Ex 2 H H ^(i)Pr H3-Me—Ph F: 406 117 Ex 2 H H

H 3-Me—Ph F: 477 118 Ex 2 H H (CH₂)₂OH H 3-Me—Ph F: 408 119 Ex 2 Cl H MeH 3-Me—Ph F: 412 120 Pre 4 Cl Cl Me H

F: 476; NMR1: 1.30(3H, d, J = 6.3 Hz), 2.76-2.80(5H, m), 8.65(1H, s)Sal: HCl 121 Ex 2 Cl Cl

H 3-Me—Ph F: 511 Sal: 2HCl 122 Pre 4 Cl Cl (CH₂)₂OH H

F: 506 Sal: HCl

TABLE 15

Pre Syn —Y—B Dat  3 Pre 3 —cHex F: 356  46 — —CH₂-(2,6-F₂—Ph) F: 400  47— —CH₂-(2-MeO—Ph) F: 394  48 — —CH₂—tBu F: 344  49 — —(CH₂)₂—CHMe₂ F:344  50 — —cPen F: 342  51 — —CH₂—2Py F: 365  52 — —CH₂-(2-Cl—Ph) F: 398 54 —

F: 417  53 — —CH₂-(3-Me—Ph) F: 378  55 — —(CH₂)₂—SEt F: 362  56 ——CH₂-(3,5-F₂—Ph) F: 400  57 — —CH₂-(2,3-Cl₂—Ph) F: 433  70 — —(2-Me—Ph)F: 364  71 — —(3-MeS—Ph) F: 396  72 — —(4-Me—Ph) F: 364  73 ——(3,5-Me₂—Ph) F: 378 123 Pre 3 —Ph F: 350 124 Pre 3 —Bn F: 364 125 Pre 3

F: 463 Sal: 2HCl 126 Pre 3 —CH₂—cHex F: 370

TABLE 16

Pre Syn —Y—B Dat  13 Pre 13 iPr F: 371; NMR1: 3.00-3.03 (6H, d, J = 6.8Hz), 3.55-3.57(4H, m), 8.50(1H, s)  14 Pre 14 cPr F: 369 127 Pre 13CH₂—iPr F: 385 128 Pre 13 tBu F: 385 Sal: 2HCl 129 Ex 3 3-Me—Ph F: 419Sal: 2HCl 130 Pre 14 cPen F: 397 131 Pre 14 cHex F: 411 132 Pre 14 cHepF: 425 133 Pre 14 cOct F: 439 134 Pre 14

F: 423 135 Pre 14

F: 427 136 Pre 14

F: 427 137 Pre 14

F: 502 138 Pre 14

F: 488 139 Pre 14

F: 488 140 Pre 14

F: 459 141 Pre 14 (CH₂)₂OMe F: 387 142 Pre 14 CH₂—CN F: 368 143 Pre 14

F: 440 144 Pre 14 CH₂—CH═CH₂ F: 369 145 Pre 14 CH₂—C≡CH F: 367 146 Pre14

F: 413 147 Pre 14

F: 401 148 Pre 14 CH₂CF₃ F: 411 149 Pre 14 CH₂—cPr F: 383 150 Pre 14(CH₂)₂Ph F: 433 151 Pre 14 C(Me)₂Ph F: 447 152 Pre 14

F: 433 153 Pre 14

F: 433 154 Pre 14

F: 449 155 Pre 14

F: 449 156 Pre 14

F: 439 157 Pre 14

F: 439 158 Pre 14

F: 387 159 Pre 14

F: 387

TABLE 17

Pre Syn —Y—B Dat  12 Pre 12 cHex F: 397; NMR1: 1.95-1.98(2H, m),3.02-3.04(4H, m), 8.47(1H, s) 160 Pre 13

F: 413 161 Pre 13

F: 475 162 Pre 13

F: 445; NMR1: 2.97-3.03(m, 4H), 5.36-5.44(m, 1H), 8.56(s, 1H) 163 Pre 13

F: 431; NMR1: 2.96-3.06(m, 4H), 5.60-5.70(m, 1H), 8.54(s, 1H) 164 Pre 13C(Me)₂—Ph F: 433; NMR1: 1.67(6H, s), 2.94- 3.02(4H, m), 8.49(1H, s) 165Pre 13 CH(Me)-(2-F—Ph) F: 437; NMR1: 8.52(1H, s), 3.73- 3.76(4H, m),1.49(3H, d, J = 6.9 Hz) 166 Pre 13 CH(2-F—Ph)—CH₂OH F: 453; NMR1:5.13-5.16(1H, m), 6.78(2H, d, J = 9.3 Hz), 8.51(1H, s) 167 Ex 3 3-Me—PhF: 405 Sal: HCl 168 Ex 3 3-F₃C—Ph F: 459 169 Ex 3 CH₂CF₃ F: 397 170 Ex 3

F: 435 171 Ex 3

F: 419 172 Pre 13 CH(Me)-(2-F—Ph) F: 437; NMR1: 1.49(3H, d, J = 6.9 Hz),6.79(2H, d, J = 9.1 HZ), 8.52(1H, s) 173 Pre 13 (CH₂)₂—Ph F: 419; NMR1:3.62-3.70(2H, m), 3.72-3.76(4H, m), 8.48(1H, s)

TABLE 18

Pre Syn R⁴ —Y—B Dat  5 Pre 5  AcNHCH₂ 3-Me—Ph F: 391  6 Pre 6 H₂NCONHCH₂ 3-Me—Ph F: 392  7 Pre 7  MeNHCH₂ 3-Me—Ph F: 363  8 Pre 8 

3-Me—Ph F: 462 Sal: 3HCl  9 Pre 9  Me₂NCH₂ 3-Me—Ph F: 377 Sal: 2HCl  10Pre 10 HO(CH₂)₂ 3-Me—Ph F: 364  11 Pre 11 MeO Bn F: 350  15 Pre 15 H BnF: 320 174 Pre 4  HO(CH₂)₂

F: 394 175 Pre 4  HO(CH₂)₂

F: 389 176 Pre 4  HO(CH₂)₂ 3,5-F₂—Ph F: 386 177 Pre 4  HO(CH₂)₂2,5-F₂—Ph F: 386; NMR1: 2.70(2H, t, J = 7.3 Hz), 6.84-6.90(1H, m),8.77(1H, s) 178 Pre 4  HO(CH₂)₂ 2,6-F₂—Ph F: 386 179 Pre 4  HO(CH₂)₂3,4-F₂—Ph F: 386 180 Pre 4  HO(CH₂)₂ 2,4-F₂—Ph F: 386; NMR1: 2.68(2H, t,J = 7.3 Hz), 7.03-7.07(1H, m), 8.72(1H, s) 181 Pre 5  MeSO₂NHCH₂ 3-Me—PhF: 427 182 Pre 8 

3-Me—Ph F: 393 Sal: 2HCl 183 Pre 8 

3-Me—Ph F: 363; NMR1: 1.52(3H, d, J = 6.8 Hz); 2.32(3H, s), 8.86(1H, s)Sal: 2HCl 184 Pre 10 HOCH₂ 3-Me—Ph F: 350 185 Pre 10 HO 3-Me—Ph F: 336186 Pre 10 4-OH—Ph 3-Me—Ph F: 412 187 Pre 10 Et 3-Me—Ph F: 348 188 Ex 3Et₂NCO 3-Me—Ph F: 419 Sal: HCl 189 Ex 3 Me₂NCH₂ Bn F: 377 190 Ex 3HO(CH₂)₂ Bn F: 364 Sal: HCl 191 Ex 3

3-Me—Ph F: 433 Sal: 2HCl 192 Ex 3

3-NC—Ph F: 444 193 Ex 3

Bn F: 407 Sal: 2HCl 194 Ex 3

Bn F: 465 195 Ex 3

Bn F: 467 196 Ex 3

Bn F: 445 Sal: 2HCl 197 Ex 3 (HOCH₂)₂CH Bn F: 394 198 Ex 3 HO(CH₂)₃ BnF: 378 199 Ex 3 HO(CH₂)₂ 3-Et—Ph F: 378 200 Ex 3 HOC(CF₃)₂ Bn F: 486Sal: HCl 201 Ex 3 HO(CH₂)₂ 3-NC—Ph F: 375 202 Ex 3 HO(CH₂)₂ 3-F₃C—Ph F:418 203 Ex3 HO(CH₂)₂

F: 408 204 Ex 3 HOCH₂CMe₂ 3-Me—Ph F: 392; NMR1: 1.22(6H, s), 2.30(3H,s), 8.70(1H, s) 205 Ex 3 MeO(CH₂)₂ 3-Me—Ph F: 378 206 Ex 3 HOCH₂C(Me)₂Bn F: 392; NMR1: 1.19(6H, s), 4.69(2H, d, J = 5.8 Hz), 8.54(1H, s) 207Ex 3

CH₂-(2,3,6-F₃—Ph) F: 487; NMR1: 4.04-4.12(1H, m), 4.52(1H, d, J = 4.4Hz), 4.81(2H, d, J = 5.9 Hz), 8.48(1H, s) 208 Pre 15 Me₂N Bn F: 363 209Pre 15 Et₂N Bn F: 391 210 Pre 15 MeS Bn F: 366 211 Pre 15 AcHN Bn F: 377212 Pre 15 EtO₂CCH₂ Bn F: 406 213 Pre 15 NCCH₂ Bn F: 359 214 Pre 15

Bn F: 387 215 Pre 15 HO Bn F: 336 216 Pre 15 MeSO₂ Bn F: 398 217 Pre 15Ac CH₂-(2,3,6-F₃—Ph) ESI: 416 218 Pre 15 CH₃(CH₂)₃O— CH₂-(2,3,6-F₃—Ph)ESI: 446 219 Pre 15

CH₂-(2,3,6-F₃—Ph) ESI: 497 220 Pre 15

CH₂-(2,3,6-F₃—Ph) ESI: 458 221 Pre 15 Ph—HN— CH₂-(2,3,6-F₃—Ph) ESI: 465222 Pre 15

CH₂-(2,3,6-F₃—Ph) ESI: 459 223 Pre 15 BnO—CONH— CH₂-(2,3,6-F₃—Ph) ESI:537 224 Pre 15

CH₂-(2,3,6-F₃—Ph) ESI: 454 225 Pre 15 AcN(Me)— CH₂-(2,3,6-F₃—Ph) ESI:445 226 Pre 15 EtO— CH₂-(2,3,6-F₃—Ph) ESI: 418

TABLE 19

Pre Syn R³ R⁴ R⁵ —Y—B Dat 227 Ex 3

H H 3-Me—Ph F: 433 228 Ex 3

H H 3-Me—Ph F: 405 229 Ex 3 H HO(CH₂)₂ F Bn F: 382 230 Ex 3 H

MeO Bn F: 417 231 Ex 3 F

H

F: 437; NMR1: 1.50(3H, d, J = 6.9 Hz), 2.93-2.95(4H, m), 8.54(1H, s) 232Ex 3 F

H

F: 453; NMR1: 2.93-2.95 (4H, m), 5.07-5.09(1H, m), 8.33(1H, s) 233 Pre15 MeO H H Bn F: 350 234 Pre 15 Ac H H Bn F: 362 235 Pre 15 HO H H Bn F:336 236 Pre 15 HOCH₂ H H Bn F: 350 237 Pre 15 MeS H H Bn F: 366 238 Pre15 MeO MeO H Bn F: 380 239 Pre 15 Cl HO H Bn F: 370 240 Pre 15 Et₂NCH₂—HO— H

ESI: 475 241 Pre 15 Cl MeO— H

ESI: 438 242 Pre 15 BuNH—SO₂— H H

ESI: 509 243 Pre 15 F MeO— H

ESI: 422 244 Pre 15 HO—CH(Me)— H H

ESI: 418 245 Pre 15 BnOCONH— H H

ESI: 537 246 Pre 15 HOH₂C— HO— H

ESI: 420

TABLE 20

Pre Syn R¹

—Y—B Dat 247 Pre 9 Me

3-Me—Ph F: 391 248 Pre 11 H

Bn F: 392 249 Ex 3 H

Bn F: 382 250 Ex 3 H

F: 417 251 Ex 3 H

CH₂-(2-F—Ph) FN: 393; NMR1: 2.64(3H, s), 4.71(2H, d, J = 6.4 Hz),8.50(1H, s) 252 Ex 3 H

Bn F: 389 253 Ex 3 H

Bn F: 389; NMR1: 2.28(3H, s), 4.70(2H, d, J = 6.3 Hz), 8.55(1H, s) 254Ex 3 H

Bn F: 375; NMR1: 3.14-3.18(2H, m), 4.66(2H, d, J = 5.9 Hz), 8.49 (1H, s)255 Ex 3 H

Bn F: 375 256 Ex 3 H

Bn F: 389 257 Ex 3 H

Bn F: 373 258 Ex 3 H

Bn F: 403; NMR1: 2.11(3H, s), 4.69 (2H, d, J = 5.9 Hz), 8.55(1H, s) 259Pre 15 H

Bn F: 371 260 Pre 15 H

Bn F: 359 261 Pre 15 H

Bn F: 360 262 Pre 15 H

Bn F: 360 263 Pre 15 H

Bn F: 378 264 Pre 15 H

Bn F: 351 265 Ex 3 H

Bn F: 403; NMR1: 2.99(3H, s), 4.76 (2H, d, J = 5.8 Hz), 8.63(1H, s) Sal:2HCl 266 Ex 3 H

Bn F: 406 Sal: 2HCl 267 Ex 3 H

Bn F: 389; NMR1: 2.97(3H, s), 4.73 (2H, d, J = 5.9 Hz), 8.63(1H, s) Sal:2HCl 268 Ex 3 H

Bn F: 403 Sal: HCl 269 Ex 3 H

F: 445; NMR1: 2.84(3H, s), 4.86 (2H, d, J = 5.9 Hz), 8.59(1H, s) Sal:HCl 270 Pre 15 H

ESI: 427 271 Pre 15 H

ESI: 431 272 Pre 15 H

ESI: 428 273 Pre 15 H

ESI: 442 274 Pre 15 H

ESI: 482 275 Pre 15 H

ESI: 427

TABLE 21

Cmpd —Y—B 1

2

3

4

5

6

7

8

9

TABLE 22

Cmpd R⁴ 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE 23

Cmpd R⁴ Y—B 25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

TABLE 24

Cmpd R³ 67

68

69

70

71

72

TABLE 25

Cmpd B 73 2-F—Ph 74 2,5-F₂—Ph 75 3,5-F₂—Ph 76 2,6-F₂—Ph

Example 259 Measurement of STAT 6-Dependent Reporter Activity 1)Construction of STAT 6 Reactive Reporter Plasmid

A STAT 6 reporter plasmid pGL2-CI was prepared by the following method.Synthetic DNA molecules (SEQ ID NOs:1 and 2) containing a C/EBP bindingsequence contained in the germline c promoter sequence and an IL-4reactive sequence in tandem were annealed and inserted into XhoI andBglII sites of pGL2-Basic vector (Promega). Also, DATA box sequence DNAmolecules (SEQ ID NOs:3 and 4) contained in the adenovirus major latepromoter were annealed and inserted into BglII and HindIII sites of thesame vector. Thereafter, pGL2-CI/bs was constructed by inserting theblasticidin resistance gene of pUCSV-BSD (Funakoshi) into BamHI site ofthe constructed pGL2-CI.

2) Construction of STAT 6 Reporter Cell

Gene transfer of pGV-CI/bs into a human-IL-4 reactive cell FW4 cell(Mol. Cell. Biol., 14: 5433-5440) was carried out by the electroporationmethod (320 V, 960 μF/0.4 cm cuvette (Nippon Bio-Rad Laboratories)), and6 μF/ml of blasticidin (Funakoshi) was added 40 hours thereafter toselect a resistant cell. Confirmation of constant transfer of thereporter plasmid was carried out by detecting luciferase induce by IL-4stimulation. An STAT 6 reporter cell CI/FW4 was constructed by the aboveoperation.

3) STAT Reporter Assay Using CI/FW4 Cell

Stimulation of the CI/FW4 cell (1×10⁴ cells/0.1 ml) with 10 ng/ml ofhuman IL-4 (Genzyme Techne) was carried out using a white 96 well plate(Nunc). In the case of the evaluation of compounds, compound dilutionswere added to the wells before inoculating the cells into the 96 wellplate. Also, regarding the dilution of compounds, dilution was carriedout using 10% FBS-containing RPMI 1640 such that the final concentrationof DMSO in which each compound was dissolved became 0.1% or less. A 50μl portion of a cell lysis buffer (10 mM Tris-HCl pH 7.8, 0.5 mM MgCl₂,10 mM dithiothreitol and 0.1% (v/v) Triton X-100) was added 16 hoursafter the IL-4 stimulation, followed by stirring for 1 minute.Thereafter, 50 μl of a luciferase substrate solution (10 mM Tris-HCl pH7.8, 5 mM luciferin, 2 mM coenzyme A, 2 mM ATP, 0.5 mM MgCl₂ and 2 mMMg(OH)₂) was added, followed by stirring for 1 minute. Then, theluciferase activity was measured using ML3000 luminometer (DynatechLaboratories, Inc). Inhibitory activities of tested compounds wereevaluated in which the luminescence intensity (relative light unit: RLU)of measured value by ML3000 when DMSO was added instead of a compoundwas regarded as 100%, and the RLU when IL-4 stimulation was not carriedout as 0%.

The results are shown in the following Table 26. Ex indicates Examplecompound number, Pre indicates Production Example compound number, Inhindicates inhibition ratio when each compound is 1 μM or 0.1 μM, and NTindicates not tested. Also, ref 1 and ref 2 are compounds disclosed inWO 99/31073 as the most desirable compounds, and ref 1 is the compounddescribed in Example 15(2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide) andref 2 is the compound described in Example 35(2-(cis-2-aminocyclohexylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide).

TABLE 26 Inh (%) Ex 1 μM 0.1 μM 1 100 89 2 96 48 3 100 100 35 100 95 37100 100 38 100 100 39 100 100 62 100 99 63 100 100 64 100 100 125 100100 127 100 96 128 100 94 148 100 94 180 100 91 189 100 100 190 100 100191 100 100 192 100 100 193 10 100 201 100 100 209 100 100 233 100 25244 100 97 258 100 98 Inh (%) Pre 1 μM 0.1 μM 1 100 67 9 91 33 12 100 91127 100 60 178 100 69 253 100 94 269 100 96 ref 1 19 NT ref 1 0 NT

In addition, the Example and Production Example compounds shown belowalso showed good activity similar to the compounds shown in the aboveTable 26: Examples 16, 43, 48, 58, 60, 72, 84, 96, 98, 117, 239 and 249,and Production Examples 99, 109, 204 and 265.

Example 260 Measurement of STAT 6 Tyrosine Phosphorylation

The H292 cell (ATCC) (5×10⁵ cells/0.5 ml) was inoculated into a 12 wellplate (IWAKI) and cultured overnight, and then stimulation with 10 ng/mlof human IL-4 (Genzyme techne) was carried out. In the case of theevaluation of compounds, compound dilutions were added to the wells 20minutes before the IL-4 stimulation. Also, regarding the dilution ofcompounds, dilution was carried out using 10% FBS-containing RPMI 1640such that the final concentration of DMSO in which each compound wasdissolved became 0.1% or less. This was washed three times withice-cooled physiological phosphate buffer 20 minutes after the IL-4stimulation. After the washing, 100 of a cell lysis solution (TNEbuffer: 10 mM Tris-HCl pH 7.8, 1% NP-40, 0.15 M NaCl, 1 mM EDTA, 10pg/ml aprotinin, 1 mM NaF and 1 mM Na₃VO₄) was added. The cell lysatewas recovered, and 15 μl thereof was subjected to western blotting afterSDS electrophoresis using an anti-tyrosine phosphorylated STAT 6antibody (Cell Signaling). Whether or not the tyrosine phosphorylationband of about 110 kDa is disappeared, which is IL-4stimulation-dependently detected, was judged. Also, uniform transferenceof the STAT 6 protein was confirmed using the same transfer membrane bywestern blotting which used an anti-STAT 6 antibody (Santa Cruz).

As a result of the above test, it was confirmed that tyrosinephosphorylation was inhibited by the compounds of the present invention.For example, it was completely inhibited by 1 μm of the compounds ofExamples 3, 37, 35, 60, 72, 84, 96, 98, 148, 189, 190, 191, 192, 193,201, 209 and 249 and Production Examples 99, 265 and 269.

Example 261 Measurement of Th2 Differentiation

T cells were prepared by removing nylon wool (Wako Pure ChemicalIndustries)-adhering cells from C57BL/6 mouse (Charles River Japan)spleen cells. Using a 96 well plate to which an anti-CD3ε antibody (10μg/ml) (Sederlane) had been immobilized in advance, T cells (2×10⁵cells/0.2 ml) were inoculated under stimulation with anti-CD28 antibody(1 μg/ml) (Pharmingen), IL-2 (10 ng/ml) (Peprotech) and IL-4 (10 ng/ml)(Peprotech). After 2 days of the culturing, total volume of the cellsuspension was diluted to 2 with a medium containing IL-2 (10 ng/ml) andIL-4 (10 ng/ml). The differentiation was induced by further carrying outthe culturing for 3 days. By counting the cell density, the cells afterdifferentiation were adjusted to 1×10⁶ cells/ml and inoculated into a 96well plate immobilized with the anti-CD3ε antibody, in order to induceIL-4 production. The supernatant after 24 hours of the stimulation wasrecovered, and the IL-4 production was determined by an ELISA method.The antibody used in the ELISA was purchased from Pharmingen. Also, anHRPO-labeled streptavidin (Amersham Pharmacia) was used in the detectionof biotinylated antibody, and a peroxidase color developing reagent(Sumitomo Bakelite) was used in the HRPO color development. In the caseof the evaluation of compounds, compound dilutions were added to thewells before the addition of T cells, at the time of the dilution 2 dayslater, compounds equivalent to the initial concentration were added.Also, regarding the dilution of compounds, dilution was carried outusing 10% FBS-containing RPMI 1640 such that the final concentration ofDMSO in which each compound was dissolved became 0.1% or less.Inhibitory activity of each tested compound was evaluated in which theIL-4 production when DMSO was added instead of the compound was regardedas 100%, and the IL-4 production when anti-CD28 antibody and IL-4 werenot added as 0%. The inhibition ratio of each tested compound at aconcentration of 10 nM is shown in the following Table 27.

TABLE 27 Ex Inh (%) 1 88 3 98 16 82 35 94 37 93 48 92 60 99 63 96 64 93117 85 Pre Inh (%) 99 85 ref 1 0 ref 2 0

Example 262 Evaluation Using Mouse Asthma Model

Active sensitization of female Balb/c mice were carried out byintraperitoneally administering ovalbumin (OA) and an adjuvant, aluminumhydroxide gel (alum), twice. Mice were exposed to OA by inhalation 12days after the initial sensitization and sacrificed by bloodletting 72hours after the exposure, and then alveolar lavage was carried out. Acompound to be tested or a control, 0.5% methyl cellulose, was orallyadministered for 3 days from before the OA exposure to before thealveolar lavage. After the measurement of total white blood cell countin the alveolar lavage fluid, cell smear preparations were stained tocalculate existing ratio of eosinophil based on its morphologicalcharacteristics. The total number of eosinophils was calculated from thetotal white blood cell count and existing ratio of respective kinds ofcells. As a result, hydrochloride of the compound of Example 3 inhibitedabout 60% of the antigen-induced eosinophil infiltration by its oraladministration at a dose of 1 mg/kg.

Example 263 Evaluation Using SO₂ Gas-Induced Intra-Alveolar NeutrophilInfiltration Model Mouse Asthma Model

Male C57BL/6 mice were exposed to SO₂ gas (600 ppm) for 3 hours andsacrificed by bloodletting 48 hours after the exposure, and thenalveolar lavage was carried out. After the measurement of total whiteblood cell count in the alveolar lavage fluid, cell smear preparationswere stained to calculate existing ratio of neutrophil based on itsmorphological characteristics. The number of neutrophils was calculatedfrom the total white blood cell count and existing ratio of respectivecells. A compound to be tested or a control, 0.5% methyl cellulose, wasorally administered for 2 days from just before the exposure or justafter the exposure to before the alveolar lavage. As a result,hydrochloride of the compound of Example 3 inhibited about 70% of theneutrophil infiltration by its oral administration at a dose of 10mg/kg.

Example 264 Evaluation Using Tobacco- and Ozone-Induced Intra-AlveolarNeutrophil Infiltration Model

Male B6C3F1 mice were exposed to 3% tobacco smoke 3 hours per day for 3consecutive days, from the 1st day to the 3rd day. On the 4th day, theywere exposed to 0.5 ppm of ozone for 6 hours and sacrificed bybloodletting on the 5th day, and then alveolar lavage was carried out.After the measurement of total white blood cell count in the alveolarlavage fluid, cell smear preparations were stained to calculate existingratio of neutrophil based on its morphological characteristics. Thetotal number of neutrophils was calculated from the total white bloodcell count and existing ratio of respective cells. A compound to betested or a control, 0.5% methyl cellulose, was administered just beforethe tobacco exposure or after completion of its exposure and before theozone exposure.

It is evident that the compounds useful as the active ingredients of thepresent invention have excellent inhibitory activities for STAT 6activation and Th2 differentiation from the results of theaforementioned Examples 259 to 261, and that they are useful aspreventive or therapeutic agents for respiratory diseases and the likein which STAT 6 is concerned, such as asthma, COPD and the like from theresults of the Examples 262 to 264.

1. A STAT 6 activation inhibitor which comprises adiaminopyrimidinecarboxamide derivative represented by a formula (I) ora salt thereof and a pharmaceutically acceptable carrier,

(symbols in the formula have the following meanings: A¹: CR⁵ or N, R⁵:—H, -lower alkyl, —O-lower alkyl or -halogen, A²: CR⁶ or N, R⁶: —H or-halogen, R³: —R⁰, -lower alkyl substituted with halogen, -halogen,—OR⁰, —S-lower alkyl, —CO-lower alkyl, —CO₂-lower alkyl, -loweralkylene-OH, -hetero ring, —O-hetero ring, —N(R⁰)-hetero ring, -loweralkylene-hetero ring, —O-lower alkylene-hetero ring, —S-loweralkylene-hetero ring, —SO-lower alkylene-hetero ring, —SO₂-loweralkylene-hetero ring, —N(R⁰)-lower alkylene-hetero ring, -loweralkylene-CO-hetero ring, -lower alkylene-N(R⁰)₂, —SO₂—N(R⁰)-lower alkylor -lower alkylene-N(R⁰)—CO₂-lower alkylene-phenyl, R⁰: the same ordifferent from one another, and each is H or a lower alkyl, n: 0 or 2,R⁴: (i) when n=2, —R⁰, lower alkyl substituted with halogen, —OR⁰,—N(R⁰)—CHO, —N(R⁰)—CO-lower alkyl or —N(R⁰)—SO₂-lower alkyl, (ii) whenn=0, —H, lower alkyl substituted with halogen, —OH, —NH—CHO, —CON(R⁰)₂,-lower alkylene substituted with halogen-OH, -lower alkylene-NH₂, -loweralkylene-NHCONH₂, -lower alkylene-CO₂H, -lower alkylene-CO₂-lower alkyl,-lower alkylene-CN, or —CH(lower alkylene-OH)₂, or a group representedby a formula —X^(a)—R^(4a), X^(a): single bond, —O—, —CO—, —S—, —SO₂—,—N(R⁰)—, —N(R⁰)CO—, —N(R⁰)SO₂—, -lower alkylene-O—, -loweralkylene-N(R⁰)-, -lower alkylene-N(R⁰)CO—, -lower alkylene-N(R⁰)SO₂—,-lower alkylene-N(R⁰)CO₂—, —N(CO—R⁰—, —N(SO₂-lower alkyl)-, —CON(R⁰)—,-lower alkylene-O—CO—, -lower alkenylene-CO—, -loweralkenylene-CON(R⁰)—, -lower alkenylene-CO₂—,—O—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—N(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CON(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)— or—N(R⁰)CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—, k and m, the same ordifferent from each other, and each is 0, 1, 2, 3 or 4, R^(4a): loweralkyl, phenyl, hetero ring, cycloalkyl, lower alkylene-phenyl, loweralkylene-hetero ring, lower alkylene-OH, lower alkenyl, loweralkenylene-phenyl or lower alkenylene-hetero ring, wherein the heterorings in R³ and R^(4a) may be substituted with 1 to 5 of lower alkyl,halogen, —OR⁰, —S-lower alkyl, —S(O)-lower alkyl, —SO₂-lower alkyl,lower alkylene-OR⁰, —N(R⁰)₂, —CO₂R⁰, —CON(R⁰)₂, —CN, —CHO, —SO₂N(R⁰)₂,—N(R⁰)—SO₂-lower alkyl, —N(R⁰)—CO—N(R⁰)₂, —N(R⁰)—CO₂-lower alkyl,—N(R⁰)—CO₂-cycloalkyl, —NH—C(═NH)—NH-lower alkyl, —NH—C(═N—CN)—NH-loweralkyl, hetero ring (said hetero ring may be substituted with 1 to 5substituents selected from lower alkyl, OH and lower alkylene-OH),-lower alkylene-NH—C(═NN)—NH₂, —O-phenyl, —CO-phenyl, —N(R⁰)—CO-loweralkyl, —N(R⁰)—CO-lower alkylene-N(R⁰)₂, -lower alkylene-N(R⁰)—CO-loweralkylene-N(R⁰)₂, —CO—N(R⁰)-lower alkylene-N(R⁰)₂, —CO-loweralkylene-N(R⁰)₂, —CO-lower alkylene-CO₂R⁰, -lower alkylene-N(R⁰)₂,-lower alkylene-CO₂R⁰, -lower alkylene-CO—N(R⁰)₂, -loweralkylene-N(R⁰)—CO-lower alkyl, -lower alkylene-N(R⁰)—CO₂-lower alkyl,-lower alkylene-N(R⁰)—SO₂-lower alkyl, -lower alkylene-hetero ring (saidhetero ring may be substituted with 1 to 5 substituents selected fromlower alkyl, OH and lower alkylene-OH), lower alkylene-O-loweralkylene-phenyl, ═N—O—R⁰ or oxo, and phenyl and cycloalkyl may besubstituted with 1 to 5 of lower alkyl, OH, O-lower alkyl or N(R⁰)₂, andwherein the lower alkylene in R³, R⁴, R^(4a) and X^(a) may besubstituted with 1 to 5 of —OR⁰, —CO₂R⁰, —CON(R⁰)₂, —N(R⁰)₂, —N(R⁰)COR⁰or hetero ring, or R³ and R⁴ may together form *—N(R⁷)—(CH₂)₂—,*—(CH₂)₂—N(R⁷)—, *—CH₂—N(R⁷)—CH₂—, *—N(R⁷)—(CH₂)₃—, *—(CH₂)₃—N(R⁷)—,*—CH₂—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—CH₂—, *—C(O)—N(R⁷)—(CH₂)₂—,*—(CH₂)₂—N(R⁷)—C(O)—, *—N(R⁷)—CH═CH—, *—CH═CH—N(R⁷)—, *—N═CH—CH═CH—,*—CH═N—CH═CH—, *—CH═CH—N═CH—, *—CH═CH—CH═N—, *—N═CH—CH═N—, *—CH═N—N═CH—,*—N(R⁷)—N═CH—, *—CH═N—N(R⁷)—, *—O—(CH₂)—O—, *—O—(CH₂)₂—O—,*—O—(CH₂)₃—O—, *—O—(CH₂)₂—N(R⁷)—, *—(CH₂)₂—C(O)—, *—CH═CH—C(O)—O— or*—N═C(CF₃)—NH—, wherein * indicates bonding to the position shown by R³,R⁷: —H, -lower alkyl or —CO-lower alkyl, B: H, lower alkenyl, loweralkynyl, lower alkyl substituted with halogen, CN, S-lower alkyl, arylwhich may have a substituent(s), cycloalkyl which may have asubstituent(s) or hetero ring which may have a substituent(s), Y: singlebond; or lower alkylene which may be substituted with 1 to 5 groupsselected from halogen, OH, O-lower alkyl, —NH₂, —NH-lower alkyl and—N(lower alkyl)₂, and R¹ and R²: the same or different from each other,and each represents H, lower alkyl or O-lower alkyl which may have asubstituent(s)).
 2. The STAT 6 activation inhibitor described in claim1, which is a Th2 cell differentiation inhibitor.
 3. Adiaminopyrimidinecarboxamide derivative represented by a formula (Ia) ora salt thereof,

(symbols in the formula have the following meanings: A¹: CR⁵ or N, R⁵:—H, -lower alkyl, —O-lower alkyl or -halogen, R³: —R⁰, -lower alkylsubstituted with halogen, -halogen, —OR⁰, —S-lower alkyl, —CO-loweralkyl, —CO₂-lower alkyl, -lower alkylene-OH, -saturated hetero ring,—X^(b)-heteroaryl, —X^(b)-saturated hetero ring, —X^(b)-heteroaryl,-lower alkylene-N(R⁰)₂, —SO₂—N(R⁰)-lower alkyl or -loweralkylene-N(R⁰)—CO₂-lower alkylene-phenyl, X^(b): -lower alkylene-,—O-lower alkylene-, —S-lower alkylene-, —SO-lower alkylene-, —SO₂-loweralkylene-, —N(R⁰)-lower alkylene- or -lower alkylene-CO—, R⁰: the sameor different from one another, and each represents H or a lower alkyl,R⁴: —X^(a)-saturated hetero ring, -lower alkylene-saturated hetero ringor -lower alkenylene-saturated hetero ring, X^(a): single bond, —O—,—CO—, —S—, —SO₂—, —N(R⁰)—, —N(R⁰)CO—, —N(R⁰)SO₂—, -lower alkylene-O—,-lower alkylene-N(R⁰)—, -lower alkylene-N(R⁰)CO— or -loweralkylene-N(R⁰)SO₂—, -lower alkylene-N(R⁰)CO₂—, —N(CO—R⁰)—, —N(SO₂-loweralkyl)-, —CON(R⁰)—, -lower alkylene-O—CO—, -lower alkenylene-CO—, -loweralkenylene-CON(R⁰)—, -lower alkenylene-CO₂—,—O—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—N(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m),—CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CON(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)— or—N(R⁰)CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—, k and m: the same ordifferent from each other, and each is 0, 1, 2, 3 or 4, wherein thesaturated hetero rings in R³ and R^(4a) may be substituted with 1 to 5of lower alkyl, halogen, —OR⁰, —S-lower alkyl, —S(O)-lower alkyl,—SO₂-lower alkyl, lower alkylene-OR⁰, —N(R⁰)₂, —CO₂R⁰, —CON(R⁰)₂, —CN,—CHO, —SO₂N(R⁰)₂, —N(R⁰)—SO₂-lower alkyl, —N(R⁰)—CO—N(R⁰)₂,—N(R⁰)—CO₂-lower alkyl, —N(R⁰)—CO₂-cycloalkyl, —NH—C(═NH)—NH-loweralkyl, —NH—C(═N—CN)—NH-lower alkyl, saturated hetero ring (said heteroring may be substituted with 1 to 5 substituents selected from loweralkyl, OH and lower alkylene-OH), heteroaryl, -loweralkylene-NH—C(═NN)—NH₂, —O-phenyl, —CO-phenyl, —N(R⁰)—CO-lower alkyl,—N(R⁰)—CO-lower alkylene-N(R⁰)₂, -lower alkylene-N(R⁰)—CO-loweralkylene-N(R⁰)₂, —CO—N(R⁰)-lower alkylene-N(R⁰)₂, —CO-loweralkylene-N(R⁰)₂, —CO-lower alkylene-CO₂R⁰, -lower alkylene-N(R⁰)₂,-lower alkylene-CO₂R⁰, -lower alkylene-CO—N(R⁰)₂, -loweralkylene-N(R⁰)—CO-lower alkyl, -lower alkylene-N(R⁰)—CO₂-lower alkyl,-lower alkylene-N(R⁰)—SO₂-lower alkyl, -lower alkylene-hetero ring (saidhetero ring may be substituted with 1 to 5 substituents selected fromlower alkyl, OH and lower alkylene-OH), -lower alkylene-O-loweralkylene-phenyl, ═N—O—R⁰ or oxo, and phenyl and cycloalkyl may besubstituted with 1 to 5 of lower alkyl, OH, O-lower alkyl or N(R⁰)₂, andwherein the lower alkylene in R³, R⁴ and X^(a) may be substituted with 1to 5 of —OR⁰, —CO₂R⁰, —CON(R⁰)₂, —N(R⁰)₂, —N(R⁰)COR⁰ or hetero ring, orR³ and R⁴ may together form *—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—,*—CH₂—N(R⁷)—CH₂—, *—N(R⁷)—(CH₂)₃—, *—(CH₂)₃—N(R⁷)—, *—CH₂—N(R⁷)—(CH₂)₂—,*—(CH₂)₂—N(R⁷)—CH₂—, *—C(O)—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—C(O)—,*—N(R⁷)—CH═CH—, *—CH═CH—N(R⁷)—, *—N═CH—CH═CH—, *—CH═N—CH═CH—,*—CH═CH—N═CH—, *—CH═CH—CH═N—, —N═CH—CH═N—, *—CH═N—N═CH—, *—N(R⁷)—N═CH—,*—CH═N—N(R⁷)—, *—O—CH₂—O—, *—O—(CH₂)₂—O—, *—O—(CH₂)₃—O—,*—O—(CH₂)₂—N(R⁷)—, *—(CH₂)₂—C(O)—, *—CH═CH—C(O)—O— or *—N═C(CF₃)—NH—,wherein * indicates bonding to the position shown by R³, R⁷: —H, -loweralkyl or —CO-lower alkyl, B: aryl which may have a substituent(s) orheteroaryl which may have a substituent(s), and R¹ and R²: the same ordifferent from each other, and each represents H, lower alkyl or O-loweralkyl which may have a substituent(s)).
 4. Adiaminopyrimidinecarboxamide derivative represented by a formula (Ib) ora salt thereof,

(symbols in the formula have the following meanings: A¹: CR⁵ or N, R⁵:—H; -lower alkyl, —O-lower alkyl or -halogen, R³: -saturated hetero ringor —X^(b)-saturated hetero ring, X^(b): -lower alkylene-, —O—, —N(R⁰)—,—O-lower alkylene-, —S-lower alkylene-, —SO-lower alkylene-, —SO₂-loweralkylene-, —N(R⁰)-lower alkylene- or -lower alkylene-CO—, R⁰: the sameor different from one another, and each represents H or a lower alkyl,R⁴: —H, -lower alkyl substituted with halogen, —OH, —NH—CHO, —CON(R⁰)₂,-lower alkylene substituted with halogen-OH, -lower alkylene-NH₂, -loweralkylene-NHCONH₂, -lower alkylene-CO₂H, -lower alkylene-CO₂-lower alkyl,-lower alkylene-CN, —CH(lower alkylene-OH)₂ or —X^(a)—R^(4a), X^(a):single bond, —O—, —CO—, —S—, —SO₂—, —N(R⁰)—, —N(R⁰)CO—, —N(R⁰)SO₂—,-lower alkylene-O—, -lower alkylene-N(R⁰)—, -lower-alkylene-N(R⁰)CO— or-lower alkylene-N(R⁰)SO₂—, -lower alkylene-N(R⁰)CO₂—, —N(CO—R⁰)—,—N(SO₂-lower alkyl)-, —CON(R⁰)—, -lower alkylene-O—CO—, -loweralkenylene-CO—, -lower alkenylene-CON(R⁰)—, -lower alkenylene-CO₂—,—O—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—N(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CO—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—,—CON(R⁰)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)— or—N(R⁰)CO)—(CH₂)_(k)-cycloalkylene-(CH₂)_(m)—, k and m: the same ordifferent from each other, and each is 0, 1, 2, 3 or 4, R^(4a): loweralkyl, phenyl, heteroaryl, cycloalkyl, lower alkylene-phenyl, loweralkylene-heteroaryl, lower alkylene-OH, lower alkenyl, loweralkenylene-phenyl or lower alkenylene-heteroaryl, wherein the saturatedhetero ring and heteroaryl in R³ and R^(4a) may be substituted with 1 to5 of lower alkyl, halogen, —OR⁰, —S-lower alkyl, —S(O)-lower alkyl,—SO₂-lower alkyl, lower alkylene-OR⁰, —N(R⁰)₂, —CO₂R⁰, —CON(R⁰)₂, —CN,—CHO, —SO₂N(R⁰)₂, —N(R⁰)—SO₂-lower alkyl, —N(R⁰)—CO—N(R⁰)₂,—N(R⁰)—CO₂-lower alkyl, —N(R⁰)—CO₂-cycloalkyl, —NH—C(═NH)—NH-loweralkyl, —NH—C(═N—CN)—NH-lower alkyl, hetero ring (said hetero ring may besubstituted with 1 to 5 substituents selected from lower alkyl, OH andlower alkylene-OH), -lower alkylene-NH—C(═NN)—NH₂, —O-phenyl,—CO-phenyl, —N(R⁰)—CO-lower alkyl, —N(R⁰)—CO-lower alkylene-N(R⁰)₂,-lower alkylene-N(R⁰)—CO-lower alkylene-N(R⁰)₂, —CO—N—(R⁰)-loweralkylene-N(R⁰)₂, —CO-lower alkylene-N(R⁰)₂, —CO-lower alkylene-CO₂R⁰,-lower alkylene-N(R⁰)₂, -lower alkylene-CO₂R⁰, -loweralkylene-CO—N(R⁰)₂, -lower alkylene-N(R⁰)—CO-lower alkyl, -loweralkylene-N(R⁰)—CO₂-lower alkyl, -lower alkylene-N(R⁰)—SO₂-lower alkyl,-lower alkylene-hetero ring (said hetero ring may be substituted with 1to 5 substituents selected from lower alkyl, OH and lower alkylene-OH),-lower alkylene-O-lower alkylene-phenyl, ═N—O—R⁰ or oxo, and phenyl andcycloalkyl may be substituted with 1 to 5 of lower alkyl, OH, O-loweralkyl or N(R⁰)₂, or the lower alkylene in R³, R⁴, R^(4a) and X^(a) maybe substituted with 1 to 5 of —OR⁰, —CO₂R⁰, —CON(R⁰)₂, —N(R⁰)₂,—N(R⁰)COR⁰ or hetero ring, or R³ and R⁴ may together form*—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—, *—CH₂—N(R⁷)—CH₂—, *—N(R⁷)—(CH₂)₃—,*—(CH₂)₃—N(R⁷)—, *—CH₂—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—CH₂—,*—C(O)—N(R⁷)—(CH₂)₂—, *—(CH₂)₂—N(R⁷)—C(O)—, *—N(R⁷)—CH═CH—,*—CH═CH—N(R⁷)—, *—N═CH—CH═CH—, *—CH═N—CH═CH—, *—CH═CH—N═CH—,*—CH═CH—CH═N—, *—N═CH—CH═N—, *—CH═N—N═CH—, *—N(R⁷)—N═CH—, *—CH═N—N(R⁷)—,*—O—CH₂—O—, *—O—(CH₂)₂—O—, *—O—(CH₂)₃—O—, *—O—(CH₂)₂—N(R⁷)—,*—(CH₂)₂—C(O)—, *—CH═CH—C(O)—O— or *—N═C(CF₃)—NH—, wherein * indicatesbonding to the position shown by R³, R⁷: —H, -lower alkyl or —CO-loweralkyl, B: aryl which may have a substituent(s) or heteroaryl which mayhave a substituent(s), and R¹ and R² the same or different from eachother, and each represents H, lower alkyl or O-lower alkyl which mayhave a substituent (s)).
 5. A diaminopyrimidinecarboxamide derivativerepresented by a formula (Ic) or a salt thereof,

(symbols in the formula have the following meanings: R⁵: —H or -halogen,B: phenyl which may have 1 to 3 substituents selected from lower alkyland halogen, Y: single bond or —CH₂—, and R¹ and R²: the same ordifferent from each other, and each represents H or lower alkyl whichmay have a substituent(s)).
 6. A diaminopyrimidinecarboxamide selectedfrom the group consisting of4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,2-[(4-morpholin-4-ylphenyl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,4-[(2,6-difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,4-[(2,6-difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,4-[(2-methoxybenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,4-[(2-fluoro-6-methoxybenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide,2-({4-[(1-methylpiperidin-3-yl)oxy]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-({4-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-{[4-(2-morpholin-4-ylethoxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,2-{[4-(β-D-glucopyranosyloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide,4-benzylamino-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide,4-benzylamino-2-{[2-(3,5-dichloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide,2-[(4-morpholin-4-ylphenyl)amino]-4-[(2-thienylmethyl)amino]pyrimidine-5-carboxamide,4-{[(3-chloro-2-thienyl)methyl]amino}-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamideand2-{[3-(2-morpholin-4-ylethyl)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamideor salts thereof.
 7. A pharmaceutical composition which comprises thediaminopyrimidinecarboxamide derivative or a salt thereof described inclaims 3 to 6 and a pharmaceutically acceptable carrier.
 8. Thecomposition described in claim 7, which is a preventive or therapeuticagent for respiratory diseases.
 9. The composition described in claim 8,which is a preventive or therapeutic agent for asthma.
 10. Thecomposition described in claim 8, which is a preventive or therapeuticagent for a chronic obstructive pulmonary disease.
 11. Use of adiaminopyrimidinecarboxamide derivative represented by the generalformula (I) described in claim 1, or a salt thereof, for the manufactureof an STAT 6 activation inhibitor.
 12. Use of adiaminopyrimidinecarboxamide derivative represented by the generalformula (I) described in claim 1, or a salt thereof, for the manufactureof a Th2 cell differentiation inhibitor.
 13. A method for inhibitoryactivity for STAT 6 activation, which comprises administering aneffective amount of a diaminopyrimidinecarboxamide derivativerepresented by the general formula (I) described in claim 1, or a saltthereof, to a mammal.
 14. A method for inhibitory activity for Th2 celldifferentiation, which comprises administering an effective amount of adiaminopyrimidinecarboxamide derivative represented by the generalformula (I) described in claim 1, or a salt thereof, to a mammal.